2021/03/31 更新

写真a

タベタ コウイチ
多部田 康一
TABETA Koichi
所属
教育研究院 医歯学系 歯学系列 教授
医歯学総合研究科 口腔生命科学専攻 摂食環境制御学 教授
職名
教授
外部リンク

学位

  • 博士(歯学) ( 2001年3月   新潟大学 )

研究分野

  • ライフサイエンス / 保存治療系歯学  / 歯周病学

経歴(researchmap)

  • 新潟大学大学院 医歯学総合研究科 歯周診断・再建学分野   教授

    2018年10月 - 現在

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  • UT Southwestern Medical Center   Visiting Assistant Prof.

    2016年11月 - 2017年10月

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  • 新潟大学研究推進機構   Institute for Research Promotion   研究准教授

    2016年10月 - 2018年9月

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  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   助教

    2012年12月 - 2018年9月

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  • 新潟大学   研究推進機構 超域学術院   准教授

    2011年12月 - 2012年11月

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  • 新潟大学   超域研究機構   准教授

    2007年12月 - 2011年10月

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  • 新潟大学   歯学部 歯学科   助教

    2005年4月 - 2007年11月

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  • The Scripps Research Institute   Research fellow

    2002年1月 - 2005年3月

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  • 新潟大学   歯学部附属病院   医員

    2001年4月 - 2001年12月

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▶ 全件表示

経歴

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   教授

    2018年10月 - 現在

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   助教

    2012年12月 - 2018年9月

  • 新潟大学   研究推進機構 超域学術院   准教授

    2011年4月 - 2012年11月

  • 新潟大学   超域研究機構   准教授

    2007年4月 - 2011年3月

  • 新潟大学   歯学部附属病院   医員

    2001年4月 - 2001年12月

所属学協会

  • 特定非営利活動法人 日本歯周保存学会

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  • 特定非営利活動法人 日本免疫学会

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  • 国際歯科研究学会

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  • 特定非営利活動法人 日本歯周病学会

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論文

  • Association among periodontitis severity, anti-agalactosyl immunoglobulin G titer, and the disease activity of rheumatoid arthritis. 国際誌

    Chihiro Kaneko, Tetsuo Kobayashi, Satoshi Ito, Noriko Sugita, Akira Murasawa, Hajime Ishikawa, Koichi Tabeta

    Journal of periodontal research   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The aim of the present study was to evaluate the association between the periodontal and serological parameters and the disease activity of rheumatoid arthritis (RA) and between the anti-agalactosyl immunoglobulin G (IgG) titer and periodontitis severity. The objective was also to assess the effect of supragingival scaling on the serological parameters in patients with RA. BACKGROUND: The periodontal and serological parameters in relation to the autoimmune inflammatory response have been linked to RA disease activity. However, the association of the anti-agalactosyl IgG titer with RA disease activity and periodontitis severity has not been elucidated. METHODS: The periodontal, rheumatologic, and serological data were collected from 127 patients with RA in a retrospective cohort study. Of the 127 patients, 21 had been randomly assigned to receive oral hygiene instruction and supragingival scaling. The anti-agalactosyl IgG titer was determined by an electrochemiluminescence immunoassay. RESULTS: The patients with a moderate to high RA disease activity showed significantly higher levels of probing depth (PD), clinical attachment level, anti-cyclic citrullinated peptide IgG, and anti-agalactosyl IgG titer and greater mean percentages of severe periodontitis than those with a low RA disease activity (p < .05 for all). Both univariate and multivariate analyses revealed a significantly positive correlation between the PD and RA disease activity (p = .009 and p = .001), between the anti-agalactosyl IgG titer and RA disease activity (p = .002 and p < .001), and between the anti-agalactosyl IgG titer and PD (p < .001 for both). Supragingival scaling significantly decreased the anti-agalactosyl IgG titer (p = 0.03). CONCLUSION: The PD and anti-agalactosyl IgG titer are positively interrelated, both of which are correlated positively with RA disease activity and influenced by supragingival scaling in patients with RA.

    DOI: 10.1111/jre.12867

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  • Estimation of the Periodontal Inflamed Surface Area by Simple Oral Examination. 国際誌

    Yoshiaki Nomura, Toshiya Morozumi, Yukihiro Numabe, Yorimasa Ogata, Yohei Nakayama, Tsutomu Sugaya, Toshiaki Nakamura, Soh Sato, Shogo Takashiba, Satoshi Sekino, Nobuo Yoshinari, Nobuhiro Hanada, Naoyuki Sugano, Mitsuo Fukuda, Masato Minabe, Makoto Umeda, Koichi Tabeta, Keiso Takahashi, Kazuyuki Noguchi, Hiroaki Kobayashi, Hideki Takai, Fusanori Nishimura, Fumihiko Suzuki, Erika Kakuta, Atsutoshi Yoshimura, Atsushi Saito, Taneaki Nakagawa

    Journal of clinical medicine10 ( 4 )   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The periodontal inflamed surface area (PISA) is a useful index for clinical and epidemiological assessments, since it can represent the inflammation status of patients in one contentious variable. However, calculation of the PISA is difficult, requiring six point probing depth measurements with or without bleeding on probing on 28 teeth, followed by data input in a calculation program. More simple methods are essential for screening periodontal disease or in epidemiological studies. In this study, we tried to establish a convenient partial examination method to estimate PISA. Cross-sectional data of 254 subjects who completed active periodontal therapy were analyzed. Teeth that represent the PISA value were selected by an item response theory approach. The maxillary second molar, first premolar, and lateral incisor and the mandibular second molar and lateral incisor were selected. The sum of the PISAs of these teeth was significantly correlated with the patient's PISA (R2 = 0.938). More simply, the sum of the maximum values of probing pocket depth with bleeding for these teeth were also significantly correlated with the patient's PISA (R2 = 0.6457). The simple model presented in this study may be useful to estimate PISA.

    DOI: 10.3390/jcm10040723

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  • A large-scale observational study to investigate the current status of diabetic complications and their prevention in Japan (JDCP study 6): baseline dental and oral findings.

    Koji Inagaki, Takeshi Kikuchi, Toshihide Noguchi, Akio Mitani, Keiko Naruse, Tatsuaki Matsubara, Masamitsu Kawanami, Jun Negishi, Yasushi Furuichi, Eiji Nemoto, Satoru Yamada, Hiromasa Yoshie, Koichi Tabeta, Sachiyo Tomita, Atsushi Saito, Sayaka Katagiri, Yuichi Izumi, Hiroshi Nitta, Takanori Iwata, Yukihiro Numabe, Matsuo Yamamoto, Nobuo Yoshinari, Tsuyoshi Fujita, Hidemi Kurihara, Fusanori Nishimura, Toshihiko Nagata, Hiromichi Yumoto, Toru Naito, Kazuyuki Noguchi, Koichi Ito, Shinya Murakami, Rimei Nishimura, Naoko Tajima

    Diabetology international12 ( 1 ) 52 - 61   2021年1月

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    記述言語:英語  

    Japan Diabetes Complication and Prevention prospective (JDCP) study was conducted to examine the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6099 patients with diabetes (range, 40-75 years) who had been treated as outpatients between 2007 and 2009. The mean number of present teeth at baseline was 19.8 and women with type 2 diabetes had fewer teeth than men with type 2 diabetes. Within the previous year, 17% of all patients had lost teeth. At baseline, 32% had experienced gingival swelling, 69% had brushed more than twice a day, 37% had used interdental cleaning aids, and 43% had undergone regular dental checkups. Multiple logistic regression analysis indicated that type 1 patients with HbA1c ≥ 7.0% were at higher risk of having fewer than 20 teeth (odds ratio [OR] 2.38; 95% confidence interval [CI] 1.25-4.78), and type 2 patients with HbA1c ≥ 8.0% also were at high risk of having fewer than 20 teeth (OR 1.16; 95% CI 1.00-1.34), after adjustment for nine possible confounding factors. In conclusion, patients with diabetes were found to be at high risk of tooth loss, and the poorer the glycemic control, the higher the risk of tooth loss in these patients.

    DOI: 10.1007/s13340-020-00465-3

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  • Ingestion of Porphyromonas gingivalis exacerbates colitis via intestinal epithelial barrier disruption in mice 国際誌

    Takahiro Tsuzuno, Naoki Takahashi, Miki Yamada-Hara, Mai Yokoji-Takeuchi, Benso Sulijaya, Yukari Aoki-Nonaka, Aoi Matsugishi, Kyoko Katakura, Koichi Tabeta, Kazuhisa Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH56 ( 2 ) 275 - 288   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Objective This study aimed to evaluate the effects of ingested periodontal pathogens on experimental colitis in mice and to elucidate its underlying mechanisms.Background Inflammatory bowel disease (IBD) is defined as a chronic intestinal inflammation that results in damage to the gastrointestinal tract. Epidemiological studies have shown an association between IBD and periodontitis. Although a large number of ingested oral bacteria reach gastrointestinal tract constantly, the effect of ingested periodontal pathogens on intestinal inflammation is still unknown.Methods Experimental colitis was induced by inclusion of dextran sodium sulfate solution in drinking water of the mice. Major periodontal pathogens (Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum) were administered orally every day during the experiment. The severity of colitis between the groups was compared. In vitro studies of the intestinal epithelial cell line were conducted to explore the molecular mechanisms by which periodontal pathogens affect the development of colitis.Results The oral administration of P. gingivalis significantly increased the severity of colitis when compared to other pathogens in the DSS-induced colitis model. The ingested P. gingivalis disrupted the colonic epithelial barrier by decreasing the expression of tight junction proteins in vivo. In vitro permeability assays using the intestinal epithelial cell line suggested the P. gingivalis-specific epithelial barrier disruption. The possible involvement of gingipains in the exacerbation of colitis was implied by using P. gingivalis lacking gingipains.Conclusion Porphyromonas gingivalis exacerbates gastrointestinal inflammation by directly interacting with the intestinal epithelial barrier in a susceptible host.

    DOI: 10.1111/jre.12816

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  • Rice peptide with amino acid substitution inhibits biofilm formation by Porphyromonas gingivalis and Fusobacterium nucleatum. 国際誌

    Aoi Matsugishi, Yukari Aoki-Nonaka, Mai Yokoji-Takeuchi, Miki Yamada-Hara, Yoshikazu Mikami, Manabu Hayatsu, Yutaka Terao, Hisanori Domon, Masayuki Taniguchi, Naoki Takahashi, Kazuhisa Yamazaki, Koichi Tabeta

    Archives of oral biology121   104956 - 104956   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Rice peptide has antibacterial properties that have been tested in planktonic bacterial culture. However, bacteria form biofilm at disease sites and are resistant to antibacterial agents. The aim of this study was to clarify the mechanisms of action of rice peptide and its amino acid substitution against periodontopathic bacteria and their antibiofilm effects. DESIGN: Porphyromonas gingivalis and Fusobacterium nucleatum were treated with AmyI-1-18 rice peptide or its arginine-substituted analog, G12R, under anaerobic conditions. The amount of biofilm was evaluated by crystal violet staining. The integrity of the bacteria cytoplasmic membrane was studied in a propidium iodide (PI) stain assay and transmission electron microscopy (TEM). RESULTS: Both AmyI-1-18 and G12R inhibited biofilm formation of P. gingivalis and F. nucleatum; in particular, G12R inhibited F. nucleatum at lower concentrations. However, neither peptide eradicated established biofilms significantly. According to the minimum inhibitory concentration and minimum bactericidal concentration against P. gingivalis, AmyI-1-18 has bacteriostatic properties and G12R has bactericidal activity, and both peptides showed bactericidal activity against F. nucleatum. PI staining and TEM analysis indicated that membrane disruption by G12R was enhanced, which suggests that the replacement amino acid reinforced the electostatic interaction between the peptide and bacteria by increase of cationic charge and α-helix content. CONCLUSIONS: Rice peptide inhibited biofilm formation of P. gingivalis and F. nucleatum, and bactericidal activity via membrane destruction was enhanced by amino acid substitution.

    DOI: 10.1016/j.archoralbio.2020.104956

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  • The periodontal inflamed surface area is associated with the clinical response to biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a retrospective study 査読 国際誌

    Moe Yamashita, Tetsuo Kobayashi, Satoshi Ito, Chihiro Kaneko, Akira Murasawa, Hajime Ishikawa, Koichi Tabeta

    MODERN RHEUMATOLOGY30 ( 6 ) 990 - 996   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    Objectives: We evaluated whether the periodontal inflamed surface area (PISA), a measure of the inflammatory burden posed by periodontitis, is associated with the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA). Methods: We conducted a retrospective study that collected rheumatologic and periodontal data from 54 patients with RA who had received corticosteroid, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 6 months of bDMARD therapy. After the patients were divided into two groups based on high or low PISA according to the median measurements at baseline, the rheumatologic condition was compared between the groups. Results: The patients with a low PISA showed significantly lower values for the Clinical Disease Activity Index (CDAI) (p = .008), swollen joint count (p = .02), and patient's and evaluator's global assessment (p = .01 and p = .03) and significantly greater decreases in changes in the CDAI from baseline to 6 months than the patients with a high PISA (p = .01), although these values were comparable at baseline. Both univariate and multivariate analyses revealed a significantly positive correlation between the baseline PISA and changes in the CDAI (p = .04 and p < .001). Conclusion: The PISA is associated with the clinical response to bDMARDs in patients with RA.

    DOI: 10.1080/14397595.2019.1680100

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  • Association between serum IgG antibody titers against Porphyromonas gingivalis and liver enzyme levels: A cross-sectional study in Sado Island. 国際誌

    Kei Takamisawa, Noriko Sugita, Shigeki Komatsu, Minako Wakasugi, Akio Yokoseki, Akihiro Yoshihara, Tetsuo Kobayashi, Kazutoshi Nakamura, Osamu Onodera, Takeshi Momotsu, Naoto Endo, Kenji Sato, Ichiei Narita, Hiromasa Yoshie, Koichi Tabeta

    Heliyon6 ( 11 ) e05531   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association. Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamine transferase (GGT) levels. Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant. Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

    DOI: 10.1016/j.heliyon.2020.e05531

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  • Epithelial TRPV1 channels: Expression, function, and pathogenicity in the oral cavity 査読 国際誌

    Naoki Takahashi, Takahiro Tsuzuno, Shuhei Mineo, Miki Yamada-Hara, Yukari Aoki-Nonaka, Koichi Tabeta

    JOURNAL OF ORAL BIOSCIENCES62 ( 3 ) 235 - 241   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    Background: The oral cavity serves as an entrance to the body and is therefore exposed to various exogenous stimuli, including mechanical forces, chemical agents, and bacterial components. The oral mucosa responds to these stimuli to maintain homeostasis and good oral health. The transient receptor potential vanilloid 1 (TRPV1) ion channel functions as an environment-sensing protein and is involved in a wide variety of cellular responses. Recent studies have revealed that epithelial TRPV1 ion channels in the oral cavity play pivotal roles in several pathophysiological conditions. In this review, we summarize the features of epithelial TRPV1 channels in the oral cavity and focus on their cellular function and pathogenicity with reference to related findings in other organs and tissues.Highlight: TRPV1 channels are widely expressed in epithelial cells in the oral cavity and play pivotal roles in fundamental cellular processes and disease progression.Conclusion: This review suggests that oral epithelial TRPV1 contributes to several cellular functions such as cell proliferation, barrier function, and inflammation. Further understanding of the characteristics of epithelial TRPV1 in the oral cavity may provide new insights into the prevention or treatment of diseases. (C) 2020 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.job.2020.05.005

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  • Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1. 査読 国際誌

    Tomoki Maekawa, Hikaru Tamura, Hisanori Domon, Takumi Hiyoshi, Toshihito Isono, Daisuke Yonezawa, Naoki Hayashi, Naoki Takahashi, Koichi Tabeta, Takeyasu Maeda, Masataka Oda, Athanasios Ziogas, Vasileia Ismini Alexaki, Triantafyllos Chavakis, Yutaka Terao, George Hajishengallis

    JCI insight5 ( 15 )   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Macrolide antibiotics exert antiinflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using 2 distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the antiinflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein developmental endothelial locus-1 (DEL-1). Consistent with the anti-neutrophil recruitment action of endothelial cell-derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1-dependent manner. Whereas ERM (but not other antibiotics, such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Del1-deficient mice. By interacting with the growth hormone secretagogue receptor and activating JAK2 in human lung microvascular endothelial cells, ERM induced DEL-1 transcription that was mediated by MAPK p38 and was CCAAT/enhancer binding protein-β dependent. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was dependent not only on JAK2 but also on PI3K/AKT signaling. Because DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may lead to a novel approach for the treatment of inflammatory and aging-related diseases.

    DOI: 10.1172/jci.insight.136706

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  • Nutritional Supplements and Periodontal Disease Prevention—Current Understanding 査読

    Yukari Aoki-Nonaka, Aoi Matsugishi, Hnin Yu Lwin, Naoki Takahashi, Koichi Tabeta

    Current Oral Health Reports7 ( 2 ) 154 - 164   2020年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1007/s40496-020-00261-7

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    その他リンク: http://link.springer.com/article/10.1007/s40496-020-00261-7/fulltext.html

  • Protective effect of hinokitiol against periodontal bone loss in ligature-induced experimental periodontitis in mice. 査読 国際誌

    Takumi Hiyoshi, Hisanori Domon, Tomoki Maekawa, Daisuke Yonezawa, Eiji Kunitomo, Koichi Tabeta, Yutaka Terao

    Archives of oral biology112   104679 - 104679   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    OBJECTIVE: The overall objective of this study was to investigate the effects of hinokitiol on periodontal bone loss in a murine model of experimental periodontitis and evaluate the anti-inflammatory activity of hinokitiol in vitro. DESIGN: Periodontitis was induced by tying a silk ligature around the maxillary second molar of mice for 8 days. Hinokitiol was injected once a day for 7 days into the palatal gingiva of the ligated molar. Periodontal bone loss was then assessed morphometrically in the maxillary second molar, and the number of tartrate-resistant acid phosphatase positive multinucleated giant cells around the molar was quantified. The bacterial load of the silk ligature was calculated by counting the number of colony-forming units, while the transcription levels of proinflammatory cytokine-related genes in the palatal gingiva were evaluated by real-time qPCR. The activity of hinokitiol against LPS-induced transcription of proinflammatory genes in RAW 264.7 macrophages was also examined. RESULTS: Local treatment with hinokitiol significantly inhibited the alveolar bone loss and osteoclast differentiation induced by tooth ligation. In addition, hinokitiol treatment decreased the oral bacterial load of the silk ligature and downregulated the mRNA levels of inflammatory cytokine-related genes, both in vitro and in vivo. CONCLUSION: The results indicated that hinokitiol exhibits antibacterial and anti-inflammatory activity and exerts a protective effect against periodontitis.

    DOI: 10.1016/j.archoralbio.2020.104679

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  • A bacterial metabolite induces Nrf2-mediated anti-oxidative responses in gingival epithelial cells by activating the MAPK signaling pathway 査読 国際誌

    Mai Yokoji-Takeuchi, Naoki Takahashi, Miki Yamada-Hara, Benso Sulijaya, Takahiro Tsuzuno, Yukari Aoki-Nonaka, Koichi Tabeta, Shigenobu Kishino, Jun Ogawa, Kazuhisa Yamazaki

    ARCHIVES OF ORAL BIOLOGY110   104602 - 104602   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Objective: Oxidative stress, which is defined as an imbalance between pro-oxidant and antioxidant systems, has been implicated in the development and/or progression of several inflammatory diseases, including periodontal disease. The reactive oxygen species (ROS) are the primary inducers of oxidative stress. In the induction of cytoprotective enzymes, the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling in antioxidant systems takes a main role. Notably, 10-oxo-trans-11-octadecenoic acid (KetoC), known as a bioactive metabolite generated by intestinal microorganisms, has been reported to have beneficial effects on several biological responses. Therefore, we investigated the antioxidant effect of KetoC on gingival epithelial cells (GECs) in this present study.Methods: An SV40-T antigen-transformed human gingival epithelial cell line (Epi4) was used for experiments. The alteration of anti-oxidative stress related genes was analyzed by qPCR. The cellular ROS levels were evaluated by flow cytometry. To explore its molecular mechanisms, ARE promotor activity was analyzed by luciferase assay; the involvement of mitogen-activated protein kinase (MAPK) and G protein-coupled receptor 120 (GPR120) were evaluated by Western blotting and luciferase assay, respectively.Results: KetoC significantly increased the expression of antioxidant-related genes in GECs. The level of ROS was significantly inhibited by the pretreatment of KetoC. Extracellular signal-regulated kinase (ERK) phosphorylation by KetoC promoted both the nuclear translocation of Nrf2 and its binding to the ARE in GECs. Further, GPR120 regulated the activation of KetoC induced-Nrf2-ARE signaling.Conclusion: KetoC exerts a protective function against the oxidative stress in GECs through GPR120-dependent ERK-Nrf2-ARE signaling.

    DOI: 10.1016/j.archoralbio.2019.104602

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  • 機能性糖脂質ビザンチンのStreptococcus mutansに対する抗バイオフィルム効果 スクロース濃度の影響とバイオフィルム形成関連遺伝子の発現解析 査読

    竹中 彰治, 長谷川 泰輔, 小田 真隆, 高橋 直紀, 磯野 俊仁, 大倉 直人, 山本 博文, 多部田 康一, 野杁 由一郎

    日本歯科保存学雑誌63 ( 1 ) 61 - 72   2020年2月

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    記述言語:日本語   出版者・発行元:(NPO)日本歯科保存学会  

    目的:機能性糖脂質ビザンチン(Viz-S)は,Streptococcus mutansバイオフィルムを易剥離性に変化させることで抗バイオフィルム作用を示す.本研究では,培養条件のうち,スクロース濃度を変化させたときのS.mutansの抗バイオフィルム効果,各種バイオフィルム形成関連遺伝子の転写量ならびにグルコシルトランスフェラーゼ(GTF)の発現について解析を行った.材料と方法:実験1・スクロース濃度を変化させたときのS.mutansの抗バイオフィルム効果;0.2,0.4,0.8%および1.6%のスクロース含有Brain Heart Infusion培地に,0,10,50μmol/lおよび75μmol/lのViz-Sを添加した.S.mutans UA159株を24時間嫌気培養することで,in vitroバイオフィルムモデルを作製した.リン酸緩衝生理食塩水(PBS)で2回洗浄したときの残存バイオフィルム量をクリスタルバイオレット法(CV法)により定量した.実験2・遺伝子発現動態の解析;0,10μmol/lおよび50μmol/lのViz-S存在下で24時間培養後のバイオフィルム形成菌を回収し,mRNAを抽出後,cDNAを合成した.バイオフィルム形成関連遺伝子の転写量をReal-time PCR法で解析した.実験3・ウエスタンブロッティング解析;in vitroバイオフィルムモデルを作製後,バイオフィルム形成菌と上清をそれぞれ回収した.タンパク質を抽出しSDS-PAGEを行った.疎水性膜に転写し,菌体結合型GTF(CA-GTF)抗体および遊離型GTF(CF-GTF)抗体を反応させた後,酵素標識二次抗体を反応させた.化学発光法により可視化し,タンパクの発現量を比較した.成績:10μmol/l Viz-S群のバイオフィルムは,PBSによる2回の洗浄により構造は変化しなかったが,50μmol/l Viz-S群は0.8%までのスクロース含有条件下においてバイオフィルム構造が93%減少した.1.6%のスクロース含有条件では32%のバイオフィルムが残存した.75μmol/l Viz-S群は,全スクロース濃度においてバイオフィルム形成が阻害された.10μmol/l Viz-S群は,すべての条件下において,遺伝子転写量の有意な変化はなかった.50μmol/l Viz-S群のgtfBおよびgtfC遺伝子の転写は,0.4%以上のスクロース含有条件で,コントロール群(Viz-S非含有)と比較して有意に増加したが,gtfDの転写は,すべてのスクロース含有群で0.46〜0.66倍に減少した.ウエスタンブロッティング解析で50μmol/l Viz-S群のGTFBおよびGTFCの産生量を比較したところ,コントロール群と比較して0.2%および0.4%スクロース含有条件下で有意に低下し,0.8%および1.6%スクロース含有条件下で有意に増加した.一方,GTFDは,コントロール群と比較して1/20以下に産生量が減少した.結論:50μmol/lのViz-Sは口腔粘膜への為害性が低く,殺菌ではない機序でS.mutansのバイオフィルムを剥離した.その機序の一つは,GTFDのタンパク発現を低下させることによるバイオフィルムの構造安定性の低下であった.75μmol/lのViz-Sはバイオフィルム形成を抑制した.(著者抄録)

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  • Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation. 査読 国際誌

    Takuma Misawa, Jeffrey A SoRelle, Jin Huk Choi, Tao Yue, Kuan-Wen Wang, William McAlpine, Jianhui Wang, Aijie Liu, Koichi Tabeta, Emre E Turer, Bret Evers, Evan Nair-Gill, Subhajit Poddar, Lijing Su, Feiya Ou, Liyang Yu, Jamie Russell, Sara Ludwig, Xiaoming Zhan, Sara Hildebrand, Xiaohong Li, Miao Tang, Anne R Murray, Eva Marie Y Moresco, Bruce Beutler

    Science immunology5 ( 43 )   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC ADVANCEMENT SCIENCE  

    T follicular helper cells (TFH) participate in germinal center (GC) development and are necessary for B cell production of high-affinity, isotype-switched antibodies. In a forward genetic screen, we identified a missense mutation in Prkd2, encoding the serine/threonine kinase protein kinase D2, which caused elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of serum antibodies in mice with a targeted null mutation of Prkd2 demonstrated polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was exacerbated by the T cell-dependent humoral response to immunization. GC formation and GC B cells were increased in Prkd2-/- spleens. These effects were the result of excessive cell-autonomous TFH development caused by unrestricted Bcl6 nuclear translocation in Prkd2-/- CD4+ T cells. Prkd2 directly binds to Bcl6, and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 to the cytoplasm, thereby limiting TFH development. In response to immunization, Bcl6 repressed Prkd2 expression in CD4+ T cells, thereby committing them to TFH development. Thus, Prkd2 and Bcl6 form a mutually inhibitory positive feedback loop that controls the stable transition from naïve CD4+ T cells to TFH during the adaptive immune response.

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  • M2 Phenotype Macrophages Colocalize with Schwann Cells in Human Dental Pulp. 査読 国際誌

    N Yoshiba, N Edanami, N Ohkura, T Maekawa, N Takahashi, A Tohma, K Izumi, T Maeda, A Hosoya, H Nakamura, K Tabeta, Y Noiri, K Yoshiba

    Journal of dental research   22034519894957 - 22034519894957   2020年1月

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    記述言語:英語  

    Macrophages are immune cells with high plasticity that perform many functions related to tissue injury and repair. They are generally categorized as 2 functional phenotypes: M1 (proinflammatory) and M2 (anti-inflammatory and prohealing). To investigate the role of macrophages in human dental pulp, we examined the localization and distributional alterations of macrophages in healthy dental pulp as well as during the reparative process of pulp capping with mineral trioxide aggregate (MTA) and in cariously inflamed pulp of adult human teeth. We also quantified the populations of M1/M2 macrophages in healthy dental pulp by flow cytometric analysis. CD68+CD86+ cells (M1 phenotype) and CD68+CD163+ cells (M2 phenotype) were 2.11% ± 0.50% and 44.99% ± 2.22%, respectively, of 2.96% ± 0.41% CD68+ cells (pan-macrophages) in whole healthy dental pulp. Interestingly, M2 phenotype macrophages were associated with Schwann cells in healthy pulp, during mineralized bridge formation, and in pulp with carious infections in vivo. Furthermore, the M2 macrophages associated with Schwann cells expressed brain-derived neurotrophic factor (BDNF) under all in vivo conditions. Moreover, we found that plasma cells expressed BDNF. Coculture of Schwann cells isolated from human dental pulp and human monocytic cell line THP-1 showed that Schwann cells induced M2 phenotypic polarization of THP-1 cell-derived macrophages. The THP-1 macrophages that maintained contact with Schwann cells were stimulated, leading to elongation of their cell shape and expression of M2 phenotype marker CD163 in cocultures. In summary, we revealed the spatiotemporal localization of macrophages and potent induction of the M2 phenotype by Schwann cells in human dental pulp. M2 macrophages protect neural elements, whereas M1 cells promote neuronal destruction. Therefore, suppressing the neurodestructive M1 phenotype and maintaining the neuroprotective M2 phenotype of macrophages by Schwann cells may be critical for development of effective treatment strategies to maintain the viability of highly innervated dental pulp.

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  • Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis 査読 国際誌

    Benso Sulijaya, Miki Yamada-Hara, Mai Yokoji-Takeuchi, Yumi Matsuda-Matsukawa, Kyoko Yamazaki, Aoi Matsugishi, Takahiro Tsuzuno, Keisuke Sato, Yukari Aoki-Nonaka, Naoki Takahashi, Shigenobu Kishino, Jun Ogawa, Koichi Tabeta, Kazuhisa Yamazaki

    JOURNAL OF PERIODONTOLOGY90 ( 12 ) 1470 - 1480   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Background The bioactive metabolite KetoC, generated by intestinal bacteria, exerts various beneficial effects. Nevertheless, its function in the pathogenesis of periodontitis remains unclear. Here, we investigated the effect of KetoC in a mouse model of periodontitis and explored the underlying mechanism. Methods Thirty-one 8-week-old male C57BL/6N mice were randomly divided into four groups (non-ligation, non-ligation + KetoC, ligation + Porphyromonas gingivalis, and ligation + P. gingivalis + KetoC) (n = 7/8 mice/group) and given a daily oral gavage of KetoC (15 mg/mL) or vehicle for 2 weeks. To induce periodontitis, a 5-0 silk ligature was placed on the maxillary left second molar on day 7, and P. gingivalis W83 (10(9) colony-forming unit [CFU]) was administered orally every 3 days. On day 14, all mice were euthanized. Alveolar bone destruction was determined from the level of the cemento-enamel junction to the alveolar bone crest. Moreover, bone loss level was confirmed from gingival tissue sections stained with hematoxylin and eosin. The presence of P. gingivalis was quantified using real-time polymerase chain reaction. In vitro, the bacteriostatic and bactericidal effects of KetoC were assessed by analyzing its suppressive activity on the proliferation of P. gingivalis and using a live/dead bacterial staining kit, respectively. A double-bond-deficient metabolite (KetoB) was then used to investigate the importance of double-bond structure in the antimicrobial activity of KetoC on P. gingivalis. Results In vivo, KetoC attenuated alveolar bone destruction and suppressed P. gingivalis in the periodontitis group. In vitro, KetoC (but not KetoB) downregulated the proliferation and viability of P. gingivalis in a dose-dependent manner. Conclusions KetoC reduced alveolar bone destruction in a periodontitis model via its antimicrobial function. Therefore, this bioactive metabolite may be valuable in clinical applications to support periodontal therapy.

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  • Noninvasive measurement of cell/colony motion using image analysis methods to evaluate the proliferative capacity of oral keratinocytes as a tool for quality control in regenerative medicine 査読

    Emi Hoshikawa, Taisuke Sato, Yoshitaka Kimori, Ayako Suzuki, Kenta Haga, Hiroko Kato, Koichi Tabeta, Daisuke Nanba, Kenji Izumi

    JOURNAL OF TISSUE ENGINEERING10   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SAGE PUBLICATIONS INC  

    Image-based cell/colony analyses offer promising solutions to compensate for the lack of quality control (QC) tools for noninvasive monitoring of cultured cells, a regulatory challenge in regenerative medicine. Here, the feasibility of two image analysis algorithms, optical flow and normalised cross-correlation, to noninvasively measure cell/colony motion in human primary oral keratinocytes for screening the proliferative capacity of cells in the early phases of cell culture were examined. We applied our software to movies converted from 96 consecutive time-lapse phase-contrast images of an oral keratinocyte culture. After segmenting the growing colonies, two indices were calculated based on each algorithm. The correlation between each index of the colonies and their proliferative capacity was evaluated. The software was able to assess cell/colony motion noninvasively, and each index reflected the observed cell kinetics. A positive linear correlation was found between cell/colony motion and proliferative capacity, indicating that both algorithms are potential tools for QC.

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  • The AmyI-1-18 peptide derived from rice inhibits alveolar bone resorption via suppression of inflammatory cytokine production induced by lipopolysaccharide and interleukin-1β in mice. 査読 国際誌

    Aoki-Nonaka Y, Tabeta K, Yokoji M, Matsugishi A, Matsuda Y, Takahashi N, Sulijaya B, Domon H, Terao Y, Taniguchi M, Yamazaki K

    Journal of periodontology90 ( 10 ) 1160 - 1169   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Bmp signaling in molar cusp formation. 査読 国際誌

    Fumiya Meguro, Thantrira Porntaveetus, Maiko Kawasaki, Katsushige Kawasaki, Akane Yamada, Yoshito Kakihara, Makio Saeki, Koichi Tabeta, John A Kessler, Takeyasu Maeda, Atsushi Ohazama

    Gene expression patterns : GEP32   67 - 71   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Tooth cusp is a crucial structure, since the shape of the molar tooth is determined by number, shape, and size of the cusp. Bone morphogenetic protein (Bmp) signaling is known to play a critical role in tooth development, including in initiation. However, it remains unclear whether Bmp signaling is also involved in cusp formation. To address this question, we examined cusp in two different transgenic mouse lines: mice with overexpression of Bmp4 (K14-Bmp4), and those with Bmp inhibitor, Noggin, (K14-Noggin) under keratin14 (K14) promoter. K14-Noggin mice demonstrated extra cusps, whereas reduced number of cusps was observed in K14-Bmp4 mice. To further understand how Bmps are expressed during cusp formation, we performed whole-mount in situ hybridisation analysis of three major Bmps (Bmp2, Bmp4, and Bmp7) in murine maxillary and mandibular molars from E14.5 to P3. The linear expressions of Bmp2 and Bmp4 were observed in both maxillary and mandibular molars at E14.5. The expression patterns of Bmp2 and Bmp4 became significantly different between the maxillary and mandibular molars at E16.5. At P3, all Bmps were expressed in all the cusp regions of the maxillary molar; however, the patterns differed. All Bmps thus exhibited dynamic temporo-spatial expression during the cusp formation. It could therefore be inferred that Bmp signaling is involved in regulating cusp formation.

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  • Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin-dependent neutrophil lysis. 査読 国際誌

    Takumi Hiyoshi, Hisanori Domon, Tomoki Maekawa, Kosuke Nagai, Hikaru Tamura, Naoki Takahashi, Daisuke Yonezawa, Tomohiro Miyoshi, Akihiro Yoshida, Koichi Tabeta, Yutaka Terao

    Microbiology and immunology63 ( 3-4 ) 100 - 110   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Aggregatibacter actinomycetemcomitans is considered to be associated with periodontitis. Leukotoxin (LtxA), which destroys leukocytes in humans, is one of this bacterium's major virulence factors. Amounts of neutrophil elastase (NE), which is normally localized in the cytoplasm of neutrophils, are reportedly increased in the saliva of patients with periodontitis. However, the mechanism by which NE is released from human neutrophils and the role of NE in periodontitis is unclear. In the present study, it was hypothesized that LtxA induces NE release from human neutrophils, which subsequently causes the breakdown of periodontal tissues. LtxA-treatment did not induce significant cytotoxicity against human gingival epithelial cells (HGECs) or human gingival fibroblasts (HGFs). However, it did induce significant cytotoxicity against human neutrophils, leading to NE release. Furthermore, NE and the supernatant from LtxA-treated human neutrophils induced detachment and death of HGECs and HGFs, these effects being inhibited by administration of an NE inhibitor, sivelestat. The present results suggest that LtxA mediates human neutrophil lysis and induces the subsequent release of NE, which eventually results in detachment and death of HGECs and HGFs. Thus, LtxA-induced release of NE could cause breakdown of periodontal tissue and thereby exacerbate periodontitis.

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  • Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection (vol 5, e01111, 2019) 査読 国際誌

    Mai Yokoji-Takeuchi, Koichi Tabeta, Naoki Takahashi, Kei Arimatsu, Haruna Miyazawa, Yumi Matsuda-Matsukawa, Keisuke Sato, Miki Yamada, Kazuhisa Yamazaki

    HELIYON5 ( 2 ) e01210   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    [This corrects the article DOI: 10.1016/j.heliyon.2018.e01111.].

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  • Peptides from rice endosperm protein restrain periodontal bone loss in mouse model of periodontitis 査読 国際誌

    Hikaru Tamura, Tomoki Maekawa, Hisanori Damon, Takumi Hiyoshi, Daisuke Yonezawa, Kosuke Nagai, Akihito Ochiai, Masayuki Taniguchi, Koichi Tabeta, Takeyasu Maeda, Yutaka Terao

    ARCHIVES OF ORAL BIOLOGY98   132 - 139   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Objective: Food-derived peptides have been reported to exhibit antibacterial activity against periodontal pathogenic bacteria. However, no effect has been shown on inflammation and bone resorption in periodontal pathology. The overall objective of the current study was to investigate how rice peptides influence biological defense mechanisms against periodontitis-induced inflammatory bone loss, and identify their novel functions as a potential anti-inflammatory drug.Design: The expression of inflammatory and osteoclast-related molecules was examined in mouse macrophage derived RAW 264.7 cell cultures using qPCR. Subsequently, the effect of these peptides on inflammatory bone loss in mouse periodontitis was examined using a mouse model of tooth ligation. Briefly, periodontal bone loss was induced for 7 days in mice by ligating the maxillary second molar and leaving the contralateral tooth unligated (baseline control). The mice were microinjected daily with the peptide in the gingiva until the day before euthanization. One week after the ligation, TRAP-positive multinucleated cells (MNCs) were enumerated from five random coronal sections of the ligated sites in each mouse.Results: Rice peptides REP9 and REP11 significantly inhibited transcription activity of inflammatory and osteoclast-related molecules. Local treatment with the rice peptides, in mice subjected to ligature-induced periodontitis, inhibited inflammatory bone loss, explaining the decreased numbers of osteoclasts in bone tissue sections.Conclusion: Therefore, these data suggested that the rice peptides possess a protective effect against periodontitis.

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  • Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection 査読 国際誌

    Mai Yokoji-Takeuchi, Koichi Tabeta, Naoki Takahashi, Kei Arimatsu, Haruna Miyazawa, Yumi Matsuda-Matsukawa, Keisuke Sato, Miki Yamada, Kazuhisa Yamazaki

    HELIYON5 ( 1 ) e01111   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Pro-protein convertase subtilisin/kexin type 9 (PCSK9), a secreted serine protease, regulates serum low-density lipoprotein (LDL) cholesterol levels by targeting the degradation of LDL receptor (LDLR) in the liver. Although previous reports describe elevated levels of PCSK9 in patients with periodontitis, the mechanisms that trigger this increase in serum PCSK9 levels and induce the related inflammatory response remain unclear. In an unc93b1-deficient mouse of Porphyromonas gingivalis infection, nucleic acid antigen recognition via Toll-like receptors was found to promote PCSK9 production, suggesting an indirect role for tumor necrosis factor-alpha as an inducer of PCSK9 in contrast to that reported in previous studies. Furthermore, PCSK9 production was independent of the TIR domain-containing adapter-inducing interferon-beta-dependent signaling pathway. These results indicate that changes in LDLR expression precede an increase in the serum PCSK9 level in the context of an infectious disease such as periodontitis.

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  • Gingival epithelial barrier: regulation by beneficial and harmful microbes 査読

    Naoki Takahashi, Benso Sulijaya, Miki Yamada-Hara, Takahiro Tsuzuno, Koichi Tabeta, Kazuhisa Yamazaki

    TISSUE BARRIERS7 ( 3 )   2019年

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS INC  

    The gingival epithelium acts as a physical barrier to separate the biofilm from the gingival tissue, providing the first line of defense against bacterial invasion in periodontal disease. Disruption of the gingival epithelial barrier, and the subsequent penetration of exogenous pathogens into the host tissues, triggers an inflammatory response, establishing chronic infection. Currently, more than 700 different bacterial species have been identified in the oral cavity, some of which are known to be periodontopathic. These bacteria contribute to epithelial barrier dysfunction in the gingiva by producing several virulence factors. However, some bacteria in the oral cavity appear to be beneficial, helping gingival epithelial cells maintain their integrity and barrier function. This review aims to discuss current findings regarding microorganism interactions and epithelial barrier function in the oral cavity, with reference to investigations in the gut, where this interaction has been extensively studied.

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  • Gingival epithelial barrier: regulation by beneficial and harmful microbes. 査読 国際誌

    Naoki Takahashi, Benso Sulijaya, Miki Yamada-Hara, Takahiro Tsuzuno, Koichi Tabeta, Kazuhisa Yamazaki

    Tissue barriers7 ( 3 ) e1651158 - 10   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The gingival epithelium acts as a physical barrier to separate the biofilm from the gingival tissue, providing the first line of defense against bacterial invasion in periodontal disease. Disruption of the gingival epithelial barrier, and the subsequent penetration of exogenous pathogens into the host tissues, triggers an inflammatory response, establishing chronic infection. Currently, more than 700 different bacterial species have been identified in the oral cavity, some of which are known to be periodontopathic. These bacteria contribute to epithelial barrier dysfunction in the gingiva by producing several virulence factors. However, some bacteria in the oral cavity appear to be beneficial, helping gingival epithelial cells maintain their integrity and barrier function. This review aims to discuss current findings regarding microorganism interactions and epithelial barrier function in the oral cavity, with reference to investigations in the gut, where this interaction has been extensively studied.

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  • <i>β</i> <sub>2</sub>-Microglobulin and Neutrophil Gelatinase-Associated Lipocalin, Potential Novel Urine Biomarkers in Periodontitis: A Cross-Sectional Study in Japanese. 査読 国際誌

    Nakajima M, Hosojima M, Tabeta K, Miyauchi S, Yamada-Hara M, Takahashi N, Miyazawa H, Matsuda-Matsukawa Y, Sato K, Sugita N, Komatsu Y, Ishikawa T, Akiishi K, Yamazaki K, Kato K, Saito A, Yoshie H

    International journal of dentistry2019   1394678 - 1394678   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey 査読

    K. Tabeta, M. Hosojima, M. Nakajima, S. Miyauchi, H. Miyazawa, N. Takahashi, Y. Matsuda, N. Sugita, Y. Komatsu, K. Sato, T. Ishikawa, K. Akiishi, K. Yamazaki, K. Kato, A. Saito, H. Yoshie

    Journal of Periodontal Research53 ( 3 ) 446 - 456   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Munksgaard  

    Background and Objectives: Previous reports suggest that several serum biomarkers play roles in the pathogenesis, inflammatory response, and oxidative stress in periodontitis caused by bacterial infections, linking chronic periodontitis to atherosclerotic vascular disease (ASVD). The aim of this preliminary study was to investigate, in a Japanese cross-sectional community survey, potential serum biomarkers of periodontitis that are associated with ASVD and chronic periodontitis. Material and Methods: The study cohort included a total of 108 male subjects who underwent annual health examinations. Serum biomarkers (high-sensitivity C-reactive protein [hs-CRP], proprotein convertase subtilisin/kexin type 9 [PCSK9], interleukin-6, tumor necrosis factor-α, soluble CD14, myeloperoxidase, matrix metalloproteinase-3, adiponectin, total bilirubin [TBIL], and serum lipids) were analyzed to determine their association (if any) with periodontal parameters. Aortic stiffness was evaluated using the brachial-ankle aortic pulse wave velocity (PWV) index and the cardio-ankle vascular index (CAVI). Results: The concentrations of PCSK9 and hs-CRP were increased (P =.001 and.042, respectively), and the concentration of TBIL was decreased (P =.046), in subjects with periodontal disease (determined as a probing depth of ≥4 mm in at least one site) compared with periodontally healthy subjects. The ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol and the concentrations of triglycerides, remnant-like particles-cholesterol, and oxidized LDL were elevated in subjects with periodontal disease compared with periodontally healthy subjects (P =.038,.007,.002, and.049, respectively). Multivariate regression analyses indicated that the number of sites with a pocket depth of ≥4 mm was associated with the concentration of PCSK9 and inversely associated with the concentration of TBIL independently (standardized β =.243, P =.040
    standardized β = −.443, P =.0002
    respectively). Analysis of receiver operating characteristic curves of PCSK9 indicated moderate accuracy for predicting the presence of disease sites (probing depth ≥ 4 mm) (area under the curve = 0.740). No significance in the values of PWV and CAVI was observed between subjects with periodontal disease and periodontally healthy subjects. Conclusion: In Japanese male subjects, the concentrations of serum PCSK9 and TBIL were correlated with periodontal parameters. Moreover, PCSK9 could be a candidate biomarker for diagnosing chronic periodontitis, and may also have potential to evaluate the risk for periodontitis to cause ASVD. Longitudinal studies of larger populations are necessary to confirm the exact association of periodontitis with increased serum PCSK9 and decreased TBIL.

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  • A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling 査読 国際誌

    Miki Yamada, Naoki Takahashi, Yumi Matsuda, Keisuke Sato, Mai Yokoji, Benso Sulijaya, Tomoki Maekawa, Tatsuo Ushiki, Yoshikazu Mikami, Manabu Hayatsu, Yusuke Mizutani, Shigenobu Kishino, Jun Ogawa, Makoto Arita, Koichi Tabeta, Takeyasu Maeda, Kazuhisa Yamazaki

    SCIENTIFIC REPORTS8 ( 1 ) 9008 - 9008   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Several studies have demonstrated the remarkable properties of microbiota and their metabolites in the pathogenesis of several inflammatory diseases. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a bioactive metabolite generated by probiotic microorganisms during the process of fatty acid metabolism, has been studied for its protective effects against epithelial barrier impairment in the intestines. Herein, we examined the effect of HYA on gingival epithelial barrier function and its possible application for the prevention and treatment of periodontal disease. We found that GPR40, a fatty acid receptor, was expressed on gingival epithelial cells; activation of GPR40 by HYA significantly inhibited barrier impairment induced by Porphyromonas gingivalis, a representative periodontopathic bacterium. The degradation of E-cadherin and beta-catenin, basic components of the epithelial barrier, was prevented in a GPR40-dependent manner in vitro. Oral inoculation of HYA in a mouse experimental periodontitis model suppressed the bacteria-induced degradation of E-cadherin and subsequent inflammatory cytokine production in the gingival tissue. Collectively, these results suggest that HYA exerts a protective function, through GPR40 signaling, against periodontopathic bacteria-induced gingival epithelial barrier impairment and contributes to the suppression of inflammatory responses in periodontal diseases.

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  • Pneumococcal DNA-binding proteins released through autolysis induce the production of proinflammatory cytokines via toll-like receptor 4 査読 国際誌

    Kosuke Nagai, Hisanori Domon, Tomoki Maekawa, Masataka Oda, Takumi Hiyoshi, Hikaru Tamura, Daisuke Yonezawa, Yoshiaki Arai, Mai Yokoji, Koichi Tabeta, Rie Habuka, Akihiko Saitoh, Masaya Yamaguchi, Shigetada Kawabata, Yutaka Terao

    CELLULAR IMMUNOLOGY325   14 - 22   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Streptococcus pneumoniae is a leading cause of bacterial pneumonia. Our previous study suggested that S. pneumoniae autolysis-dependently releases intracellular pneumolysin, which subsequently leads to lung injury. In this study, we hypothesized that pneumococcal autolysis induces the leakage of additional intracellular molecules that could increase the pathogenicity of S. pneumoniae. Liquid chromatography tandem-mass spectrometry analysis identified that chaperone protein DnaK, elongation factor Tu (EF-Tu), and glyceraldehyde-3phosphate dehydrogenase (GAPDH) were released with pneumococcal DNA by autolysis. We demonstrated that recombinant (r) DnaK, rEF-Tu, and rGAPDH induced significantly higher levels of interleukin-6 and tumor necrosis factor production in peritoneal macrophages and THP-1-derived macrophage-like cells via toll-like receptor 4. Furthermore, the DNA-binding activity of these proteins was confirmed by surface plasmon resonance assay. We demonstrated that pneumococcal DnaK, EF-Tu, and GAPDH induced the production of proin-flammatory cytokines in macrophages, and might cause host tissue damage and affect the development of pneumococcal diseases.

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  • Useful immunochromatographic assay of calprotectin in gingival crevicular fluid for diagnosis of diseased sites in patients with periodontal diseases. 査読 国際誌

    Jun-Ichi Kido, Shinya Murakami, Masahiro Kitamura, Manabu Yanagita, Koichi Tabeta, Kazuhisa Yamazaki, Hiromasa Yoshie, Hisashi Watanabe, Yuichi Izumi, Reiko Suda, Matsuo Yamamoto, Hideki Shiba, Tsuyoshi Fujita, Hidemi Kurihara, Mitsuharu Mizuno, Akihiro Mishima, Nobumasa Kawahara, Kazuhiro Hashimoto, Koji Naruishi, Toshihiko Nagata

    Journal of periodontology89 ( 1 ) 67 - 75   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ACAD PERIODONTOLOGY  

    BACKGROUND: Calprotectin, an inflammation-related protein, is present in gingival crevicular fluid (GCF), and the determination of calprotectin is useful for diagnosing periodontal diseases. The authors have recently developed a novel immunochromatographic (IC) chip system to determine calprotectin levels in GCF. In the present study, the usefulness of this diagnostic system is investigated in patients with periodontal diseases. METHODS: Thirty-six patients with periodontal diseases participated in this clinical test at multiple centers. Periodontitis sites (n = 118) and non-periodontitis (healthy) sites (n = 120) were selected after periodontal examination. GCF collection and periodontal examination were performed at baseline, after supragingival and subgingival scaling and root planing. Calprotectin levels in GCF were determined using a novel IC chip system and evaluated as a visual score and an IC reader value. Correlations between GCF calprotectin levels, clinical indicators, and changes in calprotectin levels by periodontal treatments were investigated. Receiver operating characteristic (ROC) analysis of IC reader value for GCF calprotectin was performed to predict periodontal diseases. RESULTS: The visual score of GCF calprotectin was highly correlated with the IC reader value. IC reader values of GCF calprotectin in the periodontitis group were higher than those of the healthy group at three dental examination stages, and they significantly decreased with periodontal treatments. Visual scores and IC reader values of GCF calprotectin were correlated to levels of clinical indicators. ROC analysis for GCF calprotectin showed an optimal cutoff value to predict periodontal diseases. CONCLUSION: Determination of GCF calprotectin using a novel IC chip system is useful for diagnosis of periodontal diseases.

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  • An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue 査読 国際誌

    Koichi Tabeta, Xin Du, Kei Arimatsu, Mai Yokoji, Naoki Takahashi, Norio Amizuka, Tomoka Hasegawa, Karine Crozat, Tomoki Maekawa, Sayuri Miyauchi, Yumi Matsuda, Takako Ida, Masaru Kaku, Kasper Hoebe, Kinji Ohno, Hiromasa Yoshie, Kazuhisa Yamazaki, Eva Marie Y. Moresco, Bruce Beutler

    SCIENTIFIC REPORTS7 ( 1 ) 11717 - 11717   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T. A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, alpha 1 chain, was responsible for the phenotype. Col1a1seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue."

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  • 新潟大学歯学部臨床実習における臨床能力評価

    藤井 規孝, 竹中 彰治, 多部田 康一, 佐藤 直子, 秋葉 奈美, 小田 陽平, 勝見 祐二, 小野 和宏, 前田 健康

    日本歯科医学教育学会雑誌33 ( 1 ) 4 - 11   2017年4月

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    記述言語:日本語   出版者・発行元:日本歯科医学教育学会  

    歯学教育を改善するために、各大学歯学部・歯科大学においてさまざまな取り組みが行われている。なかでも、診療参加型の臨床実習を充実させることは重視されており、それぞれの歯学部・歯科大学は信頼される歯科医師を輩出するという最も大きな社会的命題を果たすべく努力を続けている。新潟大学歯学部では、卒業生の質の保証を目的に、臨床実習においてACCEPT Projectを立ち上げ、「ACKPIS」と称する方法を用いて学生の臨床能力を評価してきた。ACKPISは診療を自験する学生に対し、どのような専門領域においても必要不可欠となる6つの基本項目を、それぞれの専門処置を評価課題として確認するものである。今回、ACKPISの効果を検証するために、平成28年度の受検生にアンケート調査を行った。ACKPISの基本項目は、ADEAやGDCが提唱する歯科医師に求められるコンピテンシーの中にも該当する記述がみられ、国内外で医師に対して行われている臨床能力評価法同様、診療現場でのフィードバックを含んでいることから、歯学生の臨床能力を評価するために適当であると考えられた。また、アンケート結果から、受検した学生もACKPISの必要性や重要性を認識し、受検方法や合否判定の妥当性を認めていることが明らかになった。以上のことから、ACKPISは臨床実習中の学生の臨床能力を評価するための有用な方法となり得ることが示唆された。(著者抄録)

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  • Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP 査読 国際誌

    Naoki Takahashi, Yumi Matsuda, Keisuke Sato, Petrus R. de Jong, Samuel Bertin, Koichi Tabeta, Kazuhisa Yamazaki

    SCIENTIFIC REPORTS6   29294 - 29294   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    The transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin, and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical, and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1(-/-) mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1(-/-) mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP.

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  • Microbiological and Clinical Effects of Sitafloxacin and Azithromycin in Periodontitis Patients Receiving Supportive Periodontal Therapy 査読

    Takako Nakajima, Takafumi Okui, Harue Ito, Mayuka Nakajima, Tomoyuki Honda, Yasuko Shimada, Koichi Tabeta, Kohei Akazawa, Kazuhisa Yamazaki

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY60 ( 3 ) 1779 - 1787   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC MICROBIOLOGY  

    Sitafloxacin (STFX) is a newly developed quinolone that has robust antimicrobial activity against periodontopathic bacteria. We previously reported that oral administration of STFX during supportive periodontal therapy was as effective as conventional mechanical debridement under local anesthesia microbiologically and clinically for 3 months. The aim of the present study was to examine the short-term and long-term microbiological and clinical effects of systemic STFX and azithromycin (AZM) on active periodontal pockets during supportive periodontal therapy. Fifty-one patients receiving supportive periodontal therapy were randomly allocated to the STFX group (200 mg/day of STFX for 5 days) or the AZM group (500 mg/day of AZM for 3 days). The microbiological and clinical parameters were examined until 12 months after the systemic administration of each drug. The concentration of each drug in periodontal pockets and the antimicrobial susceptibility of clinical isolates were also analyzed. The proportions of red complex bacteria, i.e., Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are the representative periodontopathic bacteria, were significantly reduced at 1 month and remained lower at 12 months than those at baseline in both the STFX and AZM groups. Clinical parameters were significantly improved over the 12-month period in both groups. An increase in the MIC of AZM against clinical isolates was observed in the AZM group. These results indicate that monotherapy with systemic STFX and AZM might be an alternative treatment during supportive periodontal therapy in patients for whom invasive mechanical treatment is inappropriate.

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  • Microbiological and Clinical Effects of Sitafloxacin and Azithromycin in Periodontitis Patients Receiving Supportive Periodontal Therapy 査読 国際誌

    Takako Nakajima, Takafumi Okui, Harue Ito, Mayuka Nakajima, Tomoyuki Honda, Yasuko Shimada, Koichi Tabeta, Kohei Akazawa, Kazuhisa Yamazaki

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY60 ( 3 ) 1779 - 1787   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC MICROBIOLOGY  

    Sitafloxacin (STFX) is a newly developed quinolone that has robust antimicrobial activity against periodontopathic bacteria. We previously reported that oral administration of STFX during supportive periodontal therapy was as effective as conventional mechanical debridement under local anesthesia microbiologically and clinically for 3 months. The aim of the present study was to examine the short-term and long-term microbiological and clinical effects of systemic STFX and azithromycin (AZM) on active periodontal pockets during supportive periodontal therapy. Fifty-one patients receiving supportive periodontal therapy were randomly allocated to the STFX group (200 mg/day of STFX for 5 days) or the AZM group (500 mg/day of AZM for 3 days). The microbiological and clinical parameters were examined until 12 months after the systemic administration of each drug. The concentration of each drug in periodontal pockets and the antimicrobial susceptibility of clinical isolates were also analyzed. The proportions of red complex bacteria, i.e., Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are the representative periodontopathic bacteria, were significantly reduced at 1 month and remained lower at 12 months than those at baseline in both the STFX and AZM groups. Clinical parameters were significantly improved over the 12-month period in both groups. An increase in the MIC of AZM against clinical isolates was observed in the AZM group. These results indicate that monotherapy with systemic STFX and AZM might be an alternative treatment during supportive periodontal therapy in patients for whom invasive mechanical treatment is inappropriate.

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  • Resveratrol suppresses the inflammatory responses of human gingival epithelial cells in a SIRT1 independent manner 査読

    T. Minagawa, T. Okui, N. Takahashi, T. Nakajima, K. Tabeta, S. Murakami, K. Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH50 ( 5 ) 586 - 593   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background and ObjectiveIn periodontitis, chronic infection by periodontopathic bacteria induces uncontrolled inflammation, which leads to periodontal tissue destruction. Human gingival epithelial cells (HGECs) constitute a critical first line of defense against periodontopathic bacteria, both as a physical barrier and as regulators of inflammation. Resveratrol, a polyphenol found in grapes and red wine, reportedly has anti-inflammatory properties. Therefore, we investigated the effects of resveratrol on the Porphyromonas gingivalis-induced inflammatory responses of HGECs and their mechanism.
    Material and MethodsWe stimulated the HGEC line, epi 4, with live or heat-killed P.gingivalis in the presence of resveratrol, and analyzed expressions of the interleukin-8, monocyte chemoattractant protein-1 and interleukin-1 genes. We determined the involvement of SIRT1 in the effect of resveratrol using sirtinol (a SIRT1 inhibitor) or SIRT1 knockdown. We also examined whether the effects were mediated by activation of AMP-activated kinase, suppression of reactive oxygen species, or inhibition of nuclear factor-B (NF-B).
    ResultsResveratrol treatment decreased the expression of inflammatory cytokines and slightly increased the expression of SIRT1. However, neither SIRT1 inhibition nor SIRT1 knockdown counteracted its anti-inflammatory effects. Although resveratrol did not affect AMP-activated kinase activation or reactive oxygen species production, it slightly suppressed NF-B translocation when cells were stimulated with heat-killed P.gingivalis.
    ConclusionResveratrol suppressed the inflammatory responses of P.gingivalis-stimulated HGECs, probably by inhibiting NF-B signaling but independent of SIRT1.

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  • Epithelial TRPV1 Signaling Accelerates Gingival Epithelial Cell Proliferation 査読

    N. Takahashi, Y. Matsuda, H. Yamada, K. Tabeta, T. Nakajima, S. Murakami, K. Yamazaki

    JOURNAL OF DENTAL RESEARCH93 ( 11 ) 1141 - 1147   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SAGE PUBLICATIONS INC  

    Transient receptor potential cation channel subfamily V member 1 (TRPV1), a member of the calcium-permeable thermosensitive transient receptor potential superfamily, is a sensor of thermal and chemical stimuli. TRPV1 is activated by noxious heat (&gt; 43 degrees C), acidic conditions (pH &lt; 6.6), capsaicin, and endovanilloids. This pain receptor was discovered on nociceptive fibers in the peripheral nervous system. TRPV1 was recently found to be expressed by non-neuronal cells, such as epithelial cells. The oral gingival epithelium is exposed to multiple noxious stimuli, including heat and acids derived from endogenous and exogenous substances; however, whether gingival epithelial cells (GECs) express TRPV1 is unknown. We show that both TRPV1 mRNA and protein are expressed by GECs. Capsaicin, a TRPV1 agonist, elevated intracellular Ca2+ levels in the gingival epithelial cell line, epi 4. Moreover, TRPV1 activation in epi 4 cells accelerated proliferation. These responses to capsaicin were inhibited by a specific TRPV1 antagonist, SB-366791. We also observed GEC proliferation in capsaicin-treated mice in vivo. No effects were observed on GEC apoptosis by epithelial TRPV1 signaling. To examine the molecular mechanisms underlying this proliferative effect, we performed complementary (c)DNA microarray analysis of capsaicin-stimulated epi 4 cells. Compared with control conditions, 227 genes were up-regulated and 232 genes were down-regulated following capsaicin stimulation. Several proliferation-related genes were validated by independent experiments. Among them, fibroblast growth factor-17 and neuregulin 2 were significantly up-regulated in capsaicin-treated epi 4 cells. Our results suggest that functional TRPV1 is expressed by GECs and contributes to the regulation of cell proliferation.

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  • Age-related alterations in gene expression of gingival fibroblasts stimulated with Porphyromonas gingivalis 査読

    H. Domon, K. Tabeta, T. Nakajima, K. Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH49 ( 4 ) 536 - 543   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background and Objective: Elderly people exhibit increased susceptibility to a number of autoimmune and infectious diseases, such as periodontitis. Although aging is reportedly associated with a decline in immune function, age-related alterations in periodontal tissue have remained elusive. In the present study, we comprehensively analyzed the effect of aging on the expression of selected genes using mouse gingival fibroblasts.
    Material and Methods: Gingival fibroblasts derived from young (8 wk of age) and old (&gt;= 24 mo of age) C57BL/6 mice were stimulated with Porphyromonas gingivalis lipopolysaccharide or live P. gingivalis strain W83. Expression of cytokines/chemokines, innate immune receptors, growth factors, matrix metalloproteinases, tissue inhibitors of metalloproteinases and osteoclastogenesis-related molecules were evaluated using real-time polymerase chain reaction and ELISA for interleukin-6 and transforming growth factor-beta 1.
    Results: Gingival fibroblasts derived from old mice exhibited decreased gene expression of Il-6, Cxcl1, Tlr2, Tlr4, Irak3 (IRAK-M), Kgf, Timp1, Timp3 and Rankl under resting conditions, whereas the expression levels of Tgf beta 1, Mmp3, Mmp13 and Opg were increased. Age-related differences were also detected at the protein level. Although P. gingivalis W83 upregulated Vegf, Fgf-2 and Bmp2 expression in both young and old gingival fibroblasts, the stimulatory effect on these genes was significantly lower in old gingival fibroblasts.
    Conclusion: Our findings demonstrated that aging altered the expression of a number of genes in gingival fibroblasts. Thus, alterations in the balance of these molecules could play a critical role in periodontitis progression in the elderly.

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  • Natural killer T cells mediate alveolar bone resorption and a systemic inflammatory response in response to oral infection of mice with Porphyromonas gingivalis 査読

    Y. Aoki-Nonaka, T. Nakajima, S. Miyauchi, H. Miyazawa, H. Yamada, H. Domon, K. Tabeta, K. Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH49 ( 1 ) 69 - 76   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background and Objective: T and B cells are known to be involved in the disease process of periodontitis. However, the role of natural killer T cells in the pathogenesis of periodontitis has not been clarified.
    Materials and Methods: To examine the role of these cells, C57BL/6J (wild-type), CD1d(-/-) and alpha-galactosylceramide (alpha GC)-stimulated wild-type mice were orally infected with Porphyromonas gingivalis strain W83.
    Results: Apart from CD1d(-/-) mice, the level of alveolar bone resorption was elevated by the infection and was further accelerated in alpha GC-stimulated mice. The infection induced elevated levels of serum amyloid A and P. gingivalis-specific IgG in the sera, although the degree of elevation was much smaller in the CD1d(-/-) mice. Infection-induced RANKL elevation was only observed in aGC-stimulated mice. Although the cytokines produced by splenocytes were mainly T-helper 1 type in wild-type mice, those in alpha GC-stimulated mice were predominantly T-helper 2 type. In the liver, the infection demonstrated no effect on the gene expression for interferon-gamma, interleukin-4 and RANKL except alpha GC-stimulated mice in which the infection upregulated the gene expressions.
    Conclusion: This study is the first to show that natural killer T cells upregulated systemic and local inflammatory responses induced by oral infection with P. gingivalis, thereby contributing to the progression of alveolar bone resorption.

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  • No antigen-presentation defect in Unc93b1(3d/3d) (3d) mice Response 査読 国際誌

    Koichi Tabeta, Kasper Hoebe, Edith M. Janssen, Yu Xia, Bruce Beutler

    NATURE IMMUNOLOGY14 ( 11 ) 1102 - 1103   2013年11月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

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  • A deep intronic mutation in the ankyrin-1 gene causes diminished protein expression resulting in hemolytic anemia in mice. 査読 国際誌

    Hua Huang, PengXiang Zhao, Kei Arimatsu, Koichi Tabeta, Kazuhisa Yamazaki, Lara Krieg, Emily Fu, Tian Zhang, Xin Du

    G3 (Bethesda, Md.)3 ( 10 ) 1687 - 95   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:GENETICS SOC AM  

    Linkage between transmembrane proteins and the spectrin-based cytoskeleton is necessary for membrane elasticity of red blood cells. Mutations of the proteins that mediate this linkage result in various types of hemolytic anemia. Here we report a novel N-ethyl-N-nitrosourea-induced mutation of ankyrin-1, named hema6, which causes hereditary spherocytosis in mice through a mild reduction of protein expression. The causal mutation was traced to a single nucleotide transition located deep into intron 13 of gene Ank1. In vitro minigene splicing assay revealed two abnormally spliced transcripts containing cryptic exons from fragments of Ank1 intron 13. The inclusion of cryptic exons introduced a premature termination codon, which leads to nonsense-mediated decay of the mutant transcripts in vivo. Hence, in homozygous mice, only wild-type ankyrin-1 is expressed, albeit at 70% of the level in wild-type mice. Heterozygotes display a similar hereditary spherocytosis phenotype stemming from intermediate protein expression level, indicating the haploinsufficiency of the mutation. Weakened linkage between integral transmembrane protein, band 3, and underlying cytoskeleton was observed in mutant mice as the result of reduced high-affinity binding sites provided by ankyrin-1. Hema6 is the only known mouse mutant of Ank1 allelic series that expresses full-length canonical ankyrin-1 at a reduced level, a fact that makes it particularly useful to study the functional impact of ankyrin-1 quantitative deficiency.

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  • Profiling biomarkers in gingival crevicular fluid using multiplex bead immunoassay 査読 国際誌

    Yasuko Shimada, Koichi Tabeta, Noriko Sugita, Hiromasa Yoshie

    ARCHIVES OF ORAL BIOLOGY58 ( 6 ) 724 - 730   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Objective: Biomarkers in gingival crevicular fluid (GCF) have been investigated; however, measurements were limited by the small sample volume available. The aim of this study was to determine the levels of 40 different cytokines and chemokines in GCF samples.Design: Eleven patients with generalised chronic periodontitis participating in a supportive periodontal therapy programme with remaining probing pocket depths (PDs) of >5 mm were enrolled. One healthy and two diseased sites were sampled in each subject. Forty biomarkers in GCF were examined using a multiplex bead immunoassay. Porphyromonas gingivalis from the diseased sites was quantified by real-time polymerase chain reaction.Results: Twenty-six biomarkers were detected in the GCF samples using the multiplex bead immunoassay. The levels of nine biomarkers were significantly different between the diseased and healthy sites after adjustment with Bonferroni's correction. The level of 26 biomarkers in diseased sites was compared between bleeding on probing (BOP)-positive and BOP-negative sites. Interleukin (IL)-1 beta and interferon-inducible protein (IP)-10 levels were significantly higher in BOP-positive diseased sites than BOP-negative diseased sites after adjustment for multiple comparisons (IL-1 beta, p = 0.0007, IP-10; p = 0.0009). In addition, the levels of IL-1 beta in GCF were found to be strongly correlated with the P. gingivalis ratio (r = 0.646, p = 0.0012).Conclusion: IL-1 beta levels in GCF correlate with the PDs, BOP and the presence of P. gingivalis in subgingival plaque. Multiplex bead assays can be useful in GCF studies. These findings can help in identifying new diagnostic methods in the diagnosis of periodontal disease. (C) 2012 Elsevier Ltd. All rights reserved.

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  • ENU-induced phenovariance in mice: inferences from 587 mutations. 査読 国際誌

    Carrie N Arnold, Michael J Barnes, Michael Berger, Amanda L Blasius, Katharina Brandl, Ben Croker, Karine Crozat, Xin Du, Celine Eidenschenk, Philippe Georgel, Kasper Hoebe, Hua Huang, Zhengfan Jiang, Philippe Krebs, Diantha La Vine, Xiaohong Li, Stephen Lyon, Eva Marie Y Moresco, Anne R Murray, Daniel L Popkin, Sophie Rutschmann, Owen M Siggs, Nora G Smart, Lei Sun, Koichi Tabeta, Victoria Webster, Wataru Tomisato, Sungyong Won, Yu Xia, Nengming Xiao, Bruce Beutler

    BMC research notes5   577 - 577   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: We present a compendium of N-ethyl-N-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype. FINDINGS: In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied. CONCLUSIONS: Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice.

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  • Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice 査読

    Haruna Miyazawa, Koichi Tabeta, Sayuri Miyauchi, Yukari Aoki-Nonaka, Hisanori Domon, Tomoyuki Honda, Takako Nakajima, Kazuhisa Yamazaki

    LIPIDS IN HEALTH AND DISEASE11   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models.
    Methods: We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver.
    Results: P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection.
    Conclusions: P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.

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  • Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice 査読 国際誌

    Haruna Miyazawa, Koichi Tabeta, Sayuri Miyauchi, Yukari Aoki-Nonaka, Hisanori Domon, Tomoyuki Honda, Takako Nakajima, Kazuhisa Yamazaki

    LIPIDS IN HEALTH AND DISEASE11   121 - 121   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMC  

    Background: Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models.Methods: We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver.Results: P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection.Conclusions: P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.

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  • 歯周病安定期治療における全身抗菌療法の効果

    中島 貴子, 奥井 隆文, 伊藤 晴江, 宮内 小百合, 多部田 康一, 山崎 和久

    日本歯科医師会雑誌65 ( 5 ) 624 - 624   2012年8月

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    記述言語:日本語   出版者・発行元:(公社)日本歯科医師会  

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  • Oral infection with Porphyromonas gingivalis and systemic cytokine profile in C57BL/6.KOR-ApoEshl mice 査読

    S. Miyauchi, T. Maekawa, Y. Aoki, H. Miyazawa, K. Tabeta, T. Nakajima, K. Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH47 ( 3 ) 402 - 408   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background and Objective: Periodontal infection affects atherosclerotic diseases, such as coronary heart diseases. Mouse models have revealed that oral infection with Porphyromonas gingivalis induces changes in inflammatory-and lipid metabolism-related gene expression, regardless of the development of atherosclerotic lesions. However, the serum protein expression profile in the oral infection model has not been investigated. The present study aimed to analyse the effect of oral infection with P. gingivalis on the expression levels of multiple cytokines in the serum in apolipoprotein E-deficient mice by using a cytokine antibody array. Material and Methods: C57BL/ 6. KOR-Apoe shl mice were orally infected with P. gingivalis five times at 3 day intervals and were then killed. Splenocytes were isolated and analysed for proliferative activity and immunoglobulin G (IgG) production in response to in vitro restimulation with P. gingivalis. The expression levels of various cytokines in the sera were analysed using a mouse antibody array glass chip. Results: Splenocytes from P. gingivalis-infected mice demonstrated significantly greater proliferation and IgG production in response to P. gingivalis compared with those from sham-infected mice. Antibody array analysis revealed the selective upregulation of matrix metalloproteinase 3, intercellular adhesion molecule 1, insulin-like growth factor binding protein 2 and chemokine (C-X-C motif) ligand 7 and the downregulation of interleukin-17, tumor necrosis factor-a and L-selectin. Conclusion: These data demonstrate that oral infection with P. gingivalis induces alterations in systemic cytokine production. These cytokines could play roles in the development not only of periodontitis but also of atherosclerosis.

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  • Relationship between serum antibody titres to Porphyromonas gingivalis and hs-CRP levels as inflammatory markers of periodontitis. 査読 国際誌

    Hirotaka Miyashita, Tomoyuki Honda, Tomoki Maekawa, Naoki Takahashi, Yukari Aoki, Takako Nakajima, Koichi Tabeta, Kazuhisa Yamazaki

    Archives of oral biology57 ( 6 ) 820 - 9   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    OBJECTIVE: The present study was designed to investigate whether titres of antibody to two strains of Porphyromonas gingivalis, FDC381 and SU63, are associated with serum high-sensitivity C-reactive protein (hs-CRP) levels in Japanese periodontitis patients. DESIGN: Forty-nine patients with moderate to advanced periodontitis and 40 periodontally healthy control subjects were included in this study. hs-CRP levels and antibody titres to P. gingivalis were measured at baseline and reassessment 3-4 months after periodontal treatment in periodontitis patients as well as at the time of examination in the periodontally healthy subjects. Further, the effect of periodontal therapy, including surgical treatment and use of antibacterials on both markers, was analysed in patients. RESULTS: hs-CRP levels and antibody titres to P. gingivalis were higher in periodontitis patients than in control subjects, and they significantly decreased following periodontal treatment (p < 0.005). Also, a significant decrease in hs-CRP levels as a result of periodontal treatment was found in patients with hs-CRP levels >1 mgl(-1) at baseline (p < 0.005). Probing depth, clinical attachment level, and alveolar bone loss in patients were significantly associated with a higher antibody titre to both strains of P. gingivalis (p < 0.05), but were not related to hs-CRP levels. No relationship was observed between hs-CRP levels and tertiles as defined by titres of antibody to P. gingivalis strains FDC381 and SU63. CONCLUSIONS: Our data indicate that hs-CRP levels were independent of antibody titres to P. gingivalis in Japanese periodontitis patients.

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  • Increased serum PCSK9 concentrations are associated with periodontal infection but do not correlate with LDL cholesterol concentration. 査読 国際誌

    Haruna Miyazawa, Tomoyuki Honda, Sayuri Miyauchi, Hisanori Domon, Takafumi Okui, Takako Nakajima, Koichi Tabeta, Kazuhisa Yamazaki

    Clinica chimica acta; international journal of clinical chemistry413 ( 1-2 ) 154 - 9   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    BACKGROUND: Periodontal disease increases the risk of atherothrombotic disease, and high concentrations of low density lipoprotein (LDL) cholesterol are considered to be involved; however, the underlying mechanisms are largely unknown. Recent studies demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in circulating LDL cholesterol concentrations. The aim of the present study is to analyze serum PCSK9 concentrations and their relation to lipoprotein concentrations in periodontitis patients. METHODS: Sera were obtained from 40 periodontitis patients and 30 control subjects. PCSK9 concentrations, high-sensitivity C-reactive protein (hs-CRP), IL-6, TNF-α and Porphyromonas gingivalis antibodies were measured by ELISA, and lipid profiles were determined by a commercial laboratory. RESULTS: Periodontitis patients demonstrated significantly higher serum antibody titer to P. gingivalis and hs-CRP concentrations than control subjects, suggesting infection with P. gingivalis and a systemic inflammatory response. PCSK9 concentrations in periodontitis patients were significantly higher than those in control subjects. However, the concentrations of total and LDL cholesterols were not significantly different between periodontitis patients and control subjects. Moreover, no correlations were observed between PCSK9 concentrations and lipid profiles. CONCLUSION: Periodontal infection upregulates PCSK9 production. However, further studies are required to elucidate how periodontal infection affects PCSK9 concentrations and subsequent lipid metabolism.

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  • Increased expression of C-reactive protein gene in inflamed gingival tissues could be derived from endothelial cells stimulated with interleukin-6. 査読 国際誌

    Tomoki Maekawa, Koichi Tabeta, Keiko Kajita-Okui, Takako Nakajima, Kazuhisa Yamazaki

    Archives of oral biology56 ( 11 ) 1312 - 8   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    BACKGROUND: Epidemiological studies have suggested periodontitis as a risk factor for ischemic heart disease. High sensitive C-reactive protein (hs-CRP), a predictor of cardiovascular risk, is elevated in periodontitis patients. Therefore, local infection-induced elevation of systemic CRP could account for the relationship between the 2 diseases. However, the underlying mechanism of CRP production in the periodontal tissues has not been fully elucidated. Therefore, the aim of the present study was to clarify the mechanism of CRP production in periodontal tissues. METHODS: Gene expression of CRP in gingival biopsies was analysed by quantitative PCR. Human gingival epithelial cells (HGECs), human gingival fibroblasts (HGFBs), and human coronary artery endothelial cells (HCAECs) were characterized for CRP-producing ability by incubating with interleukin (IL)-1β, IL-6, soluble IL-6 receptor (sIL-6R), and Porphyromonas gingivalis strain W83. RESULTS: Gene expression of CRP is significantly elevated in periodontitis lesions compared with gingivitis lesions. HCAECs, but not HGECs and HGFBs, produced CRP in response to IL-6 and IL-1β in the presence of sIL-6R. In contrast to IL-6, the effect of IL-1β on CRP production was indirect via induction of IL-6. IL-1β was produced by HGECs and HGFBs with stimulation of P. gingivalis antigens. CONCLUSION: These results suggest that CRP induced locally by periodontal infection may play another role in the pathogenesis of periodontal disease, and to a much lesser extent, has the potential to modulate systemic CRP level by extra-hepatic CRP production.

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  • Effect of interleukin-17 on the expression of chemokines in gingival epithelial cells 査読 国際誌

    Naoki Takahashi, Takafumi Okui, Koichi Tabeta, Kazuhisa Yamazaki

    EUROPEAN JOURNAL OF ORAL SCIENCES119 ( 5 ) 339 - 344   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The role of interleukin (IL)-17 in cellular communication in inflammation has been well described, and a positive correlation between the severity of periodontitis and the level of IL-17 was reported. Although epithelial cells are a major target of IL-17, little is known about the effect of IL-17 on the production of chemokines by human gingival epithelial cells (HGECs). We evaluated the effects of IL-17 on the expression of CXCL8 and CCL2 by HGECs using quantitative real-time PCR and ELISA. In addition, the role of the nuclear factor (NF)-kappa B signalling pathway in the IL-17-mediated expression of chemokines was assessed using a specific inhibitor. Stimulation with IL-17 up-regulated the expression of CXCL8 mRNA but not of CCL2 mRNA in HGECs, whereas tumour necrosis factor-alpha (TNF-alpha) elevated the expression of mRNA for both chemokines. Stimulation with IL-17 up-regulated the secretion of CXCL8 protein, but not the secretion of CCL2 protein. The effect of IL-17 on CXCL8 production was suppressed using an anti-IL-17R Ig, suggesting a role for a specific receptor-ligand interaction. Inhibition of the NF-kappa B signalling pathway demonstrated that NF-kappa B activation is required for the CXCL8 expression in HGECs. In conclusion, IL-17 is involved in the regulation of the innate immune response in HGECs by inducing CXCL8 production.

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  • Elevated Antibody Titers to Porphyromonas gingivalis as a Possible Predictor of Ischemic Vascular Disease: Results from the Tokamachi-Nakasato Cohort Study 査読

    Koichi Tabeta, Naohito Tanabe, Daisuke Yonezawa, Hirotaka Miyashita, Tomoki Maekawa, Naoki Takahashi, Takafumi Okui, Takako Nakajima, Kazuhisa Yamazaki

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS18 ( 9 ) 808 - 817   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN ATHEROSCLEROSIS SOC  

    Aim: Limited epidemiological studies have investigated the relationship between ischemic vascular disease and periodontitis in non-Western populations. We investigated this relationship in a Japanese cohort by measuring serum titers of antibodies to periodontopathic bacteria.Methods: As part of the Tokamachi-Nakasato cohort study, we followed up 7021 participants regarding cardiovascular events over 5 years, and observed 99 ischemic vascular events: 66 cerebral infarctions and 33 cases of ischemic heart disease (IHD). For a nested case-control study, we selected 495 sex-and age-matched control subjects. Conditional logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of ischemic vascular events associated with antibody titers to Porphyromonas gingivalis FDC381 and SU63. Multivariable models were adjusted for traditional cardiovascular risk factors using propensity scores.Results: The highest tertile category of antibody titers to P. gingivalis FDC381 in men was significantly associated with an increased risk of cerebral infarction in only the crude model. The 2nd and 3rd tertile categories of antibody titers to P. gingivalis SU63 were significantly associated with an increased risk of cerebral infarction in men (multivariable ORs (95% CIs) were 7.12 (1.51-33.5) and 9.03 (1.97-41.5), respectively). The association was not appreciably modified when we further adjusted for serum high-sensitivity C-reactive protein levels. Antibody titers to P. gingivalis were not dose-dependently associated with the risk of IHD.Conclusion: High serum antibody titers to P. gingivalis SU63 could be a predictor of cerebral infarction in Japanese men independent of traditional risk factors and inflammation.

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  • Chronic oral infection with Porphyromonas gingivalis accelerates atheroma formation by shifting the lipid profile. 査読 国際誌

    Tomoki Maekawa, Naoki Takahashi, Koichi Tabeta, Yukari Aoki, Hirotaka Miyashita, Sayuri Miyauchi, Haruna Miyazawa, Takako Nakajima, Kazuhisa Yamazaki

    PloS one6 ( 5 ) e20240   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    BACKGROUND: Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We orally infected C57BL/6 and C57BL/6.KOR-Apoe(shl) (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages. CONCLUSIONS/SIGNIFICANCE: Periodontal infection itself does not cause atherosclerosis, but it accelerates it by inducing systemic inflammation and deteriorating lipid metabolism, particularly when underlying hyperlidemia or susceptibility to hyperlipidemia exists, and it may contribute to the development of coronary heart disease.

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  • Interleukin-1 receptor-associated kinase-M in gingival epithelial cells attenuates the inflammatory response elicited by Porphyromonas gingivalis 査読

    N. Takahashi, T. Honda, H. Domon, T. Nakajima, K. Tabeta, K. Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH45 ( 4 ) 512 - 519   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background and Objective:
    Recent studies have revealed that negative regulatory molecules, including interleukin-1 receptor-associated kinase-M (IRAK-M), control the overactivation of Toll-like receptor (TLR) signaling. The role of IRAK-M in human gingival epithelial cells (HGECs), which express TLRs, remains unclear. The present study examined the role of IRAK-M on interleukin-8 and macrophage chemoattractant protein-1 (MCP-1) expression in HGECs stimulated with Porphyromonas gingivalis and TLR ligands.
    Material and Methods:
    Primary HGECs and an SV40 T-antigen-immortalized HGEC line (epi 4) were stimulated with live or heat-killed P. gingivalis, P. gingivalis lipopolysaccharide or the synthetic lipopeptide PAM(3)CSK(4), and subsequent expression of IRAK-M, interleukin-8 and MCP-1 was evaluated at the mRNA and protein levels. The effects of IRAK-M on interleukin-8 and MCP-1 expressions were evaluated by IRAK-M-specific RNA interference (RNAi)-based loss-of-function assay.
    Results:
    All tested stimulants up-regulated the expression of IRAK-M in HGECs. The P. gingivalis lipopolysaccharide or PAM(3)CSK(4) increased MCP-1 expression, whereas live P. gingivalis down-regulated the MCP-1 expression in HGECs. However, IRAK-M RNAi increased the expression of MCP-1 irrespective of up- or down-regulation mediated by the respective stimulants. Interleukin-8 gene expression, up-regulated by all tested stimulants, was further enhanced by IRAK-M RNAi. In contrast, IRAK-M RNAi had no effect on the interleukin-8 protein levels, irrespective of the stimulant, indicating that post-translational modification, not IRAK-M, controls interleukin-8 protein expression.
    Conclusion:
    Interleukin-1 receptor-associated kinase-M appeared to have distinct regulatory roles on the interleukin-8 and MCP-1 produced by HGECs, further suggesting an important role for interleukin-8 in the immune reponse to periodontopathic bacteria.

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  • Analysis of immunostimulatory activity of Porphyromonas gingivalis fimbriae conferred by Toll-like receptor 2. 査読 国際誌

    Yukari Aoki, Koichi Tabeta, Yukitaka Murakami, Fuminobu Yoshimura, Kazuhisa Yamazaki

    Biochemical and biophysical research communications398 ( 1 ) 86 - 91   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Bacterial fimbriae are an important pathogenic factor. It has been demonstrated that fimbrial protein encoded by fimA gene (FimA fimbriae) of Porphyromonas gingivalis not only contributes to the abilities of bacterial adhesion and invasion to host cells, but also strongly stimulates host innate immune responses. However, FimA fimbriae separated from P. gingivalis ATCC 33277 using a gentle procedure showed very weak proinflammatory activity compared with previous reports. Therefore, in the present study, biological characteristics of FimA fimbriae were further analyzed in terms of proinflammatory activity in macrophages. Macrophages differentiated from THP-1 cells were stimulated with native, heat-denatured, or either proteinase- or lipoprotein lipase-treated FimA fimbriae of P. gingivalis ATCC 33277. Stimulating activities of these FimA fimbriae were evaluated by TNF-alpha-inducing activity in the macrophages. To clarify the mode of action of FimA fimbriae, anti-Toll-like receptor (TLR) 2 blocking antibody was added prior to stimulation. Weak stimulatory activity of native FimA fimbriae was enhanced by heat treatment and low-dose proteinase K treatment. Higher dose of proteinase K treatment abrogated this up-regulation. The activity of treated FimA fimbriae was suppressed by anti-TLR2 antibody, and more substantially by lipoprotein lipase treatment. These results suggest that lipoproteins or lipopeptides associated with FimA fimbriae could at least in part account for signaling via TLR2 and subsequent TNF-alpha production in macrophages.

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  • Periodontitis-associated up-regulation of systemic inflammatory mediator level may increase the risk of coronary heart disease 査読

    T. Nakajima, T. Honda, H. Domon, T. Okui, K. Kajita, H. Ito, N. Takahashi, T. Maekawa, K. Tabeta, K. Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH45 ( 1 ) 116 - 122   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Background and Objective: Although an elevation in the concentration of high-sensitivity C-reactive protein (hs-CRP) as a result of periodontal infection may account for an increased risk of developing coronary heart disease (CHD), the effect of periodontal infection on the level of hs-CRP in an otherwise healthy Japanese population has not yet been reported. The aim of the present study was to confirm, on a larger scale, our previous pilot study findings that both chronic periodontitis and subsequent periodontal treatment alter the serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha).
    Material and Methods: The concentrations of serum hs-CRP, IL-6 and TNF-alpha were measured in 78 periodontitis patients at baseline and at re-assessment, and in 40 periodontally healthy subjects at the time of examination.
    Results: The concentrations of hs-CRP and IL-6 in the sera of periodontitis patients were significantly higher than those in control subjects. By contrast, the concentration of TNF-alpha was significantly lower in periodontitis patients than in control subjects. Whereas periodontal treatment decreased the levels of serum hs-CRP and IL-6, no such effect was observed for TNF-alpha. When the patients were subdivided into four groups according to their initial concentration of hs-CRP, only the CRP and IL-6 concentrations of the highest quartile group showed a significant reduction following periodontal treatment. No significant difference in the initial clinical parameters was observed in any quartile.
    Conclusion: Although periodontal infection does affect the concentration of hs-CRP and IL-6 in serum, a subgroup of patients exist who are highly susceptible to an increased risk of CHD associated with periodontitis, suggesting that there may be subjects who have an elevated risk of CHD independent of susceptibility to periodontal tissue destruction per se.

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  • Porphyromonas gingivalis antigens and interleukin-6 stimulate the production of monocyte chemoattractant protein-1 via the upregulation of early growth response-1 transcription in human coronary artery endothelial cells. 査読 国際誌

    Tomoki Maekawa, Naoki Takahashi, Tomoyuki Honda, Daisuke Yonezawa, Hirotaka Miyashita, Takafumi Okui, Koichi Tabeta, Kazuhisa Yamazaki

    Journal of vascular research47 ( 4 ) 346 - 54   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    BACKGROUND: Individuals with periodontitis have elevated serum levels of IL-6 and C-reactive protein and have been reported to have a significantly increased risk of developing cardiovascular disease. The transcription factor early growth response factor 1 (Egr-1) has been shown to play an important role in the development and progression of atherosclerosis. However, it is not known whether periodontal infection affects the expression of Egr-1 and subsequent endothelial cells expression of monocyte chemoattractant protein (MCP)-1, a key molecule of leukocyte chemoattraction into vessels. METHODS: Human coronary artery endothelial cells (HCAECs) were stimulated with either sonicated extracts from Porphyromonas gingivalis strains 381 or SU63, or a combination of IL-6 and soluble IL-6 receptor (IL-6/sIL-6R). The expression of Egr-1, and subsequently MCP-1, was then analyzed. The role of Egr-1 on MCP-1 expression was analyzed by siRNA transfection. RESULTS: Both P. gingivalis antigens and IL-6/sIL-6R stimulations upregulated the expression of Egr-1, with a more robust effect by IL-6/sIL-6R. Increased expression of Egr-1 coincided with MCP-1 production, and Egr-1 downregulation by siRNA suppressed this effect. CONCLUSION: These results clearly suggest that periodontal infection has the potential to affect HCAECs and hence contribute to the development of subsequent atherosclerosis.

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  • Analysis of immune responses to purified recombinant antigens of periodontal pathogens. 査読 国際誌

    Koichi Tabeta, Kazuhisa Yamazaki

    Methods in molecular biology (Clifton, N.J.)666   345 - 57   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The accumulating knowledge about host-pathogen interactions in infectious diseases shows how the immune system interfaces with pathogens, and thus, helps us in understanding the pathogenesis of diseases and improving their treatment. Purified antigens are indispensable while investigating the immune response in both innate and acquired immunities. It is ideal to use native antigens purified from the host organisms in native conditions that sustain their biological activity completely. However, purification of native antigens, especially on a large scale, is technically difficult and generally time consuming. Purifying protein as a peptide-tagged fusion protein is an effective approach. Purification of a recombinant protein engineered to incorporate a polyhistidine tag at either the carboxyl or amino terminus is an established method, and it can be easily modified to obtain optimal results under different conditions. Heat-shock proteins were highly conserved during evolution and are highly homologous between prokaryotic and eukaryotic cells. Their molecular mimicry might have roles in the pathogenesis of chronic inflammatory diseases. We successfully generated histidine-tagged recombinant heat-shock proteins from the periodontopathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. The recombinant proteins allowed us to evaluate the immune response to these antigens in periodontitis patients.

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  • Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing. 査読 国際誌

    Ryutaro Fukui, Shin-ichiroh Saitoh, Fumi Matsumoto, Hiroko Kozuka-Hata, Masaaki Oyama, Koichi Tabeta, Bruce Beutler, Kensuke Miyake

    The Journal of experimental medicine206 ( 6 ) 1339 - 50   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ROCKEFELLER UNIV PRESS  

    Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1.

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  • Assessment of Chromosome 19 for Genetic Association in Severe Chronic Periodontitis 査読 国際誌

    Koichi Tabeta, Yasuko Shimada, Hideaki Tai, Yuichi Ishihara, Toshihide Noguchi, Yoshihiko Soga, Shogo Takashiba, Genki Suzuki, Terukazu Kobayashi, Akira Oka, Tetsuo Kobayashi, Kazuhisa Yamazaki, Hidetoshi Inoko, Hirornasa Yoshie

    JOURNAL OF PERIODONTOLOGY80 ( 4 ) 663 - 671   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ACAD PERIODONTOLOGY  

    Background: A genome-association study is a powerful toot for analyzing small gene effects in complex diseases such as chronic periodontitis (CP), although the cost of analysis is prohibitive. We designed a study using the DNA pooling method, which could be a breakthrough in lowering such costs. This study was conducted to assess the genetic association in severe CP in a Japanese population.Methods: We adopted a DNA pooling method by genotyping 454 densely spaced microsatellite (MS) markers in chromosome 19 as a pilot study, with the possibility of future use in a whole-genome study. This can reduce the high cost and technical burden, which is generally unavoidable in a genomic association study. Pooled DNA samples from 300 case subjects, 300 control subjects, and 200 systemically healthy subjects were screened by genotyping MS markers. The case-control association in the candidate region was analyzed by individual typing of MS and single nucleotide polymorphisms (SNPs).Results: The single MS marker allele 17 of 1902G31 was isolated in association with severe CP (P = 0.0012 for 2 x 2; P<0.046 for 2 x m, where m refers to the number of polymorphic alleles observed in a population). No other SNP or MS polymorphism hypothesized to affect biologic functions in the critical region was found in the linkage disequilibrium block analysis.Conclusions: We efficiently isolated the susceptible locus for severe CP in chromosome 19 and identified a useful marker to evaluate the risk for disease. This approach can be applied to a whole-genome study in severe CP. J Periodontol 2009;80:663-671.

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  • Up-regulation of the endoplasmic reticulum stress-response in periodontal disease. 査読 国際誌

    Hisanori Domon, Naoki Takahashi, Tomoyuki Honda, Takako Nakajima, Koichi Tabeta, Yoshimitsu Abiko, Kazuhisa Yamazaki

    Clinica chimica acta; international journal of clinical chemistry401 ( 1-2 ) 134 - 40   2009年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    BACKGROUND: Endoplasmic reticulum (ER) stress is the cell response by activation of the unfolded protein response (UPR) pathway in a variety of conditions such as infection and aging. The UPR may be associated with the pathogenesis of periodontal disease because of the induction of apoptosis and activation of nuclear factor-kappaB (NF-kappaB), a transcription factor for pro-inflammatory cytokines. However, the relationship between ER stress and periodontal disease is yet to be determined. METHODS: The expression of UPR-related molecules was analyzed by real-time polymerase chain reaction and immunohistochemistry, respectively and compared between gingivitis and periodontitis. The gene expressions were also analyzed for macrophages stimulated with lipopolysaccharides (LPS) from Escherichia coli (E. coli), and Porphyromonas gingivalis (P. gingivalis) or IFN-gamma. RESULTS: The expression levels of UPR-related genes and HSP60 were significantly higher in periodontitis compared with gingivitis lesions. However, LPS from P. gingivalis but not E. coli or IFN-gamma failed to up-regulate the gene expression in macrophage. CONCLUSIONS: An inflammatory response may have profound effect on the UPR response, particularly in periodontitis patients. Considering the histological nature of periodontitis and the link between UPR and inflammatory responses via NF-kappaB, ER stress in B cells could be another pathological mechanism underlying periodontal disease.

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  • Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria. 査読 国際誌

    Alexandra K Kiemer, Ryan H Senaratne, Jessica Hoppstädter, Britta Diesel, Lee W Riley, Koichi Tabeta, Stefan Bauer, Bruce Beutler, Bruce L Zuraw

    Journal of innate immunity1 ( 1 ) 29 - 45   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitro differentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were markedly activated by DNA isolated from attenuated mycobacterial strains (H37Ra and Mycobacterium bovis BCG) as assessed by measuring cytokine expression by real-time PCR, whereas synthetic phosphorothioate-modified oligonucleotides had a much lower potency to activate human macrophages. Intracellular replication of H37Ra was higher in macrophages isolated from TLR9-deficient mice than in macrophages from wild-type mice, whereas H37Rv showed equal survival in cells from wild-type or mutant mice. Increased bacterial survival in mouse macrophages was accompanied by altered cytokine production as determined by Luminex bead assays. In vivo infection experiments also showed differential cytokine production in TLR9-deficient mice compared to wild-type animals. Both human monocyte-derived macrophages as well as human alveolar macrophages showed reduced activation upon treatment with DNA isolated from bacteria from virulent (M. bovis and H37Rv) compared to attenuated mycobacteria. We suggest attenuated TLR9 activation contributes to the insufficient host response against virulent mycobacteria.

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  • Elevated expression of IL-17 and IL-12 genes in chronic inflammatory periodontal disease 査読

    Tomoyuki Honda, Yukari Aoki, Naoki Takahashi, Tomoki Maekawa, Takako Nakajima, Harue Ito, Koichi Tabeta, Takafumi Okui, Keiko Kajita, Hisanori Domon, Kazuhisa Yamazaki

    CLINICA CHIMICA ACTA395 ( 1-2 ) 137 - 141   2008年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Background: A number of different theories have been postulated to explain the progression of gingivitis to periodontitis in the context of the Th1/Th2 paradigm. However, no consistent results have been obtained. Th17, a new T-cell subset producing IL-17, which is implicated in many aspect of inflammatory tissue destruction, overcomes many of the discrepant findings in the studies related to the Th1/Th2 hypothesis. We compared the gene expression profile of Th17-related molecules in gingivitis and periodontitis lesions showing distinct clinical entities.Methods: Gingival tissue samples were obtained from 23 gingivitis and 24 periodontitis tissues. The gene expression was measured by using quantitative real-time PCR for IL-17A, IL-17F, CCR4, CCR6, IL-12 p35 and IL-23 p19. The difference of gene expressions between gingivitis and periodontitis was analyzed by Mann-Whitney U-test. Correlations between each gene expression were also analyzed.Results: The expression level of IL-17A was higher than that of IL-17F and a significant difference in expression between gingivitis and periodontitis was observed only for IL-17A. CCR4 and CCR6 tended to be higher in periodontitis compared with gingivitis, although the differences were not statistically significant. Whereas the gene expression of IL-12 p35 was significantly higher in periodontitis compared with gingivitis, that of IL-23 p19 was not different between the two diseases.Conclusion: This study demonstrates the elevated expression of IL-17 and IL-12 in periodontitis, i.e.. the tissue destruction form of periodontal diseases, as compared with gingivitis, and provides new insight into the T-cell mediated immunopathogenesis of periodontal disease. (C) 2008 Elsevier B.V. All rights reserved.

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  • 歯周疾患が脂質代謝に及ぼす影響

    中島 貴子, 本田 朋之, 奥井 隆文, 梶田 桂子, 土門 久哲, 高橋 直紀, 前川 知樹, 天沼 亮子, 伊藤 晴江, 多部田 康一, 山崎 和久

    日本歯科医師会雑誌61 ( 5 ) 551 - 551   2008年8月

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    記述言語:日本語   出版者・発行元:(公社)日本歯科医師会  

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  • Quantitative messenger RNA expression of Toll-like receptors and interferon-alpha 1 in gingivitis and periodontitis 査読

    K. Kajita, T. Honda, R. Amanuma, H. Domon, T. Okul, H. Ito, H. Yoshie, K. Tabeta, T. Nakajima, K. Yamazaki

    ORAL MICROBIOLOGY AND IMMUNOLOGY22 ( 6 ) 398 - 402   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    Introduction: In addition to bacteria, viruses have been reportedly implicated in periodontitis. However, the available data are confined to Toll-like receptor 2 (TLR2) and TLR4. which recognize bacterial products in periodontitis. In the present study, we investigated the expression levels of TLR5, -7, and -9 messenger RNAs (mRNAs) in addition to those of TLR2 and -4, and compared gingivitis and periodontitis. Interferon alpha 1 (IFN-alpha 1), which is important for the antiviral response, was also compared.
    Methods: Gene expression was analyzed using quantitative real-time polymerase chain reaction for 59 periodontitis and 27 gingivitis tissue samples together with viral serology in some patients. The presence of plasmacytoid dendritic cells (pDCs), a robust producer of IFN-alpha, was immunohistochemically analyzed in an additional seven periodontitis and two gingivitis specimens.
    Results: The expression levels of TLR2, -4 -7, and -9 were significantly higher in periodontitis lesions than gingivitis lesions. The expression level of TLR5 was comparable to levels of TLR2 and -4; however, no significant difference was found between gingivitis and periodontitis. Although the expression of IFN-a I mRNA was higher in periodontitis lesions compared with gingivitis lesions, the level was quite low. Only a few pDCs were found in some periodontitis specimens. No difference was found for antibody-positivity between gingivitis and periodontitis
    Conclusion: This is the first study to show that a variety of TLRs are up-regulated in periodontitis lesions compared with gingivitis lesions, suggesting that diverse microbial and possibly viral antigens are involved in the pathogenic mechanisms for periodontal diseases. However, the ligands recognized by the various TLRs in periodontal lesions remain to be determined.

    DOI: 10.1111/j.1399-302X.2007.00377.x

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  • Point mutations in the melanocortin-4 receptor cause variable obesity in mice 査読

    Thomas P. Meehan, Koichi Tabeta, Xin Du, Lanette S. Woodward, Karen Firozi, Bruce Beutler, Monica J. Justice

    MAMMALIAN GENOME17 ( 12 ) 1162 - 1171   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Mutations in the melanocortin-4 receptor (MC4R) are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure. As part of independent N-ethyl-N-nitrosourea (ENU) mutagenesis screens, two obesity mutants, Fatboy and Southbeach, were isolated. Mapping revealed linkage to the melanocortin-4 receptor (Mc4r) and sequencing found single amino acid changes in Mc4r for each line. Expression of the mutant receptors in HEK 293 cells revealed defects in receptor signaling. The mutated Fatboy receptor (I194T) shows an increase in the effective concentration necessary for 50% of maximal signaling (EC50) when stimulated with alpha-MSH. Based on competitive binding, I194T is expressed on the cell surface at lower levels than the nonmutated receptor. In contrast, Southbeach (L300P) displays minimal receptor signaling when stimulated with the natural ligand alpha-MSH or the synthetic agonist NDP-alpha-MSH. Cell surface binding is absent, which usually indicates a lack of cell surface expression. However, antibody binding to Flag-tagged receptors by flow cytometry analysis and immunofluorescence demonstrates that L300P is translocated to the plasma membrane at a level comparable to the wild-type receptor. These results indicate a correlation with remaining receptor activity and the severity of the obesity in the mice homozygous for the mutations. Southbeach has less receptor activity and becomes more obese. These mutants will serve as good models for the variability in phenotype in humans carrying mutations in the MC4R gene.

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  • Herpes simplex virus encephalitis in human UNC-93B deficiency 査読

    Armanda Casrouge, Shen-Ying Zhang, Celine Eidenschenk, Emmanuelle Jouanguy, Anne Puel, Kun Yang, Alexandre Alcais, Capucine Picard, Nora Mahfoufi, Nathalie Nicolas, Lazaro Lorenzo, Sabine Plancoulaine, Brigitte Senechal, Frederic Geissmann, Koichi Tabeta, Kasper Hoebe, Xin Du, Richard L. Miller, Benedicte Heron, Cyril Mignot, Thierry Billette de Villemeur, Pierre Lebon, Olivier Dulac, Flore Rozenberg, Bruce Beutler, Marc Tardieu, Laurent Abel, Jean-Laurent Casanova

    SCIENCE314 ( 5797 ) 308 - 312   2006年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC ADVANCEMENT SCIENCE  

    Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1 - infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-alpha/beta and -lambda antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

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  • Efficient T cell activation via a Toll-interleukin 1 Receptor-independent pathway 査読

    Edith Janssen, Koichi Tabeta, Michael J. Barnes, Sophie Rutschmann, Sara McBride, Keith S. Bahjat, Stephen P. Schoenberger, Argyrios N. Theofilopoulos, Bruce Beutler, Kasper Hoebe

    IMMUNITY24 ( 6 ) 787 - 799   2006年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Here, we describe a previously unrecognized pathway for activation of antigen-specific adaptive immune responses that was independent of Toll-Interleukin 1 Receptor signaling and directed toward detection of antigens expressed by apoptotic cells. This pathway is represented within Flt-3 Ligand-derived dendritic cells (DCs) that represent immature lymphoid DCs, but not within GM-CSF-treated bone marrow-derived dendritic cells. Exposure of these DCs to apoptotic cells resulted in production of type I interferon and favored the development of cytotoxic T cell responses. The N-Ethyl-N-Nitrosourea-induced germline mutation 3d (Unc3b1(3d/3d)) abolished both MHC class I and 11 responses elicited by this pathway, whereas a null allele of Cd36 selectively abolished class 11 responses. We propose that this mode of adaptive immune activation evolved to permit the sensitive detection of intracellular microbial infections, particularly viral infections, which frequently induce apoptotic cell death, but may also be important in transplantation, autoimmunity, and vaccine development.

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  • The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9 査読

    K Tabeta, K Hoebe, EM Janssen, Du, X, P Georgel, K Crozat, S Mudd, N Mann, S Sovath, J Goode, L Shamel, AA Herskovits, DA Portnoy, M Cooke, LM Tarantino, T Wiltshire, BE Steinberg, S Grinstein, B Beutler

    NATURE IMMUNOLOGY7 ( 2 ) 156 - 164   2006年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Here we have identified 'triple D' (3d), a recessive N-ethyl-N-nitrosourea-induced mutation and phenotype in which no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 (sensors for double-stranded RNA, single-stranded RNA and unmethylated DNA, respectively). The 3d mutation also prevented cross-presentation and diminished major histocompatibility complex class II presentation of exogenous antigen; it also caused hypersusceptibility to infection by mouse cytomegalovirus and other microbes. By positional identification, we found 3d to be a missense allele of Unc93b1, which encodes the 12-membrane-spanning protein UNC-93B, a highly conserved molecule found in the endoplasmic reticulum with multiple paralogs in mammals. Innate responses to nucleic acids and exogenous antigen presentation, which both initiate in endosomes, thus seem to depend on an endoplasmic reticulum-resident protein, which suggests communication between these organellar systems.

    DOI: 10.1038/ni1297

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  • Genetic analysis of innate immunity 査読

    Kasper Hoebe, Zhengfan Jiang, Koichi Tabeta, Xin Du, Philippe Georgel, Karine Crozat, Bruce Beutler

    ADVANCES IN IMMUNOLOGY, VOL 9191   175 - 226   2006年

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:ELSEVIER ACADEMIC PRESS INC  

    The inflammatory response to microbes-and host perception of microbes in general-is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.

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  • TLR signaling pathways: Opportunities for activation and blockade in pursuit of therapy 査読

    K. Hoebe, Z. Jiang, P. Georgel, K. Tabeta, E. Janssen, X. Du, B. Beutler

    CURRENT PHARMACEUTICAL DESIGN12 ( 32 ) 4123 - 4134   2006年

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    記述言語:英語   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    The identification of the TLRs as key sensors of microbial infection has presented a series of new targets for drug development. The TLRs are linked to the most powerful inflammatory pathways in mammals. The question arises from the start: do we wish to stimulate TLR signaling in order to eradicate specific infections and/or neoplastic diseases? Or do we wish to block TLR signaling to treat inflammatory diseases? If we accept that it would be useful to modulate TLR signaling, the next step is to identify the correct molecular target(s) for the task. Perhaps it might even be possible to exercise selectivity, modulating some aspects of TLR signaling and not others. Classical and reverse genetic analyses offer insight into the possibilities that exist, and point to specific checkpoints within signaling pathways at which modulation might normally be imposed.

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  • Genetic analysis of innate immunity 査読

    Kasper Hoebe, Zhengfan Jiang, Koichi Tabeta, Xin Du, Philippe Georgel, Karine Crozat, Bruce Beutler

    ADVANCES IN IMMUNOLOGY, VOL 9191   175 - 226   2006年

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:ELSEVIER ACADEMIC PRESS INC  

    The inflammatory response to microbes-and host perception of microbes in general-is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.

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  • An essential role for Rxr alpha in the development of Th2 responses 査読

    Du, X, K Tabeta, N Mann, K Crozat, S Mudd, B Beutler

    EUROPEAN JOURNAL OF IMMUNOLOGY35 ( 12 ) 3414 - 3423   2005年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-V C H VERLAG GMBH  

    A viable hypomorphic allele of mouse retinoid X receptor alpha (Rxr alpha) was created by random germline mutagenesis. The mutation (1273N) alters the ligand binding and heterodimerization domain, and causes a 90% decline in ligand-inducible transactivation. Homozygotes develop progressive alopecia and dermal cysts, and progressive exaggeration of Th1 and loss of Th2 responses to antigen. Th1 skewing is directly caused by aberrant function of both antigen-presenting cells and naive CD4 T cells; the predominant Th1 response to antigen is attributable to decreased suppression of regulatory T cells in mutant mouse. Dietary depletion of vitamin A in Th2-prone wildtype mice mimics the immune phenotype caused by the mutation. Hence, RXR alpha plays an important post-developmental role in the regulation of adaptive immune responses, and provides a plausible link between nutritional environment and the type of adaptive response that results from immunization.

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  • Genetic analysis of innate immunity: Identification and function of the tir adapter proteins 査読

    B Beutler, K Hoebe, P Georgel, K Tabeta, Du, X

    MECHANISMS OF LYMPHOCYTE ACTIVATION AND IMMUNE REGULATION X: INNATE IMMUNITY560   29 - 39   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

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  • Genetic analysis of innate immunity: TIR adapter proteins in innate and adaptive immune responses 査読

    B Beutler, K Hoebe, P Georgel, K Tabeta, Du, X

    MICROBES AND INFECTION6 ( 15 ) 1374 - 1381   2004年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which 10 representatives are encoded in the human genome. Our understanding of the sensing role played by the TLRs began with the positional cloning of a spontaneous mutation (Lps(d)) in the gene encoding the mammalian lipopolysaccharide (LPS) receptor. Other key innate immunity proteins have been disclosed by germline mutagenesis, and are discussed in the present review. (C) 2004 Elsevier SAS. All rights reserved.

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  • T-cell clonality to Porphyromonas gingivalis and human heat shock protein 60s in patients with atherosclerosis and periodontitis 査読

    K Yamazaki, Y Ohsawa, H Itoh, K Ueki, K Tabeta, T Oda, T Nakajima, H Yoshie, S Saito, F Oguma, M Kodama, Y Aizawa, GJ Seymour

    ORAL MICROBIOLOGY AND IMMUNOLOGY19 ( 3 ) 160 - 167   2004年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL MUNKSGAARD  

    Individuals with periodontitis have been reported to have a significantly increased risk of developing coronary heart disease. Several studies have demonstrated that the immune response to heat shock protein 60 (HSP60) may be involved in the pathogenesis of both atherosclerosis and chronic periodontitis. To investigate this possible link between these diseases, cellular and humoral immune responses to HSP60 in atherosclerosis patients were compared with those in periodontitis patients and healthy subjects using human and Porphyromonas gingivalis HSP60 (GroEL) as antigens. Antibody levels to both human and P. gingivalis HSP60s were the highest in atherosclerosis patients, followed by periodontitis patients and healthy subjects. Clonal analysis of the T cells clearly demonstrated the presence of not only human HSP60- but also P. gingivalis GroEL-reactive T-cell populations in the peripheral circulation of atherosclerosis patients. Furthermore, these HSP60-reactive T cells seemed to be present in atherosclerotic lesions in some patients. These results suggest that T-cell clones with the same specificity may be involved in the pathogenesis of the different diseases.

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  • Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection 査読

    K Tabeta, P Georgel, E Janssen, Du, X, K Hoebe, K Crozat, S Mudd, L Shamel, S Sovath, J Goode, L Alexopoulou, RA Flavell, B Beutler

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA101 ( 10 ) 3516 - 3521   2004年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Several subsets of dendritic cells have been shown to produce type I IFN in response to viral infections, thereby assisting the natural killer cell-dependent response that eliminates the pathogen. Type I IFN production can be induced both by unmethylated CpG-oligode-oxynucleotide and by double-stranded RNA. Here, we describe a codominant CpG-ODN unresponsive phenotype that results from an N-ethyl-N-nitrosourea-induced missense mutation in the Tlr9 gene (Tlr9(CpG1)). Mice homozygous for the Tlr9(CpG1) allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-alpha/beta and natural killer cell activation. We also demonstrate that both the Toll-like receptor (TLR) 9 --&gt; MyD88 and TLR3 --&gt; Trif signaling pathways are activated in vivo on viral inoculation, and that each pathway contributes to innate defense against systemic viral infection. Whereas both pathways lead to type I IFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9(CpG1) mutation alters a leucine-rich repeat motif and lies within a receptor domain that is conserved within the evolutionary cluster encompassing TLRs 7, 8, and 9. In other TLRs, including three mouse-specific TLRs described in this paper, the affected region is not represented. The phenotypic effect of the Tlr(9CpG1) allele thus points to a critical role for TLR9 in viral sensing and identifies a vulnerable amino acid within the ectodomain of three TLR proteins, essential for a ligand response.

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  • Velvet, a dominant Egfr mutation that causes wavy hair and defective eyelid development in mice 査読

    Du, X, K Tabeta, K Hoebe, HQ Liu, N Mann, S Mudd, K Crozat, S Sovath, XH Gong, B Beutler

    GENETICS166 ( 1 ) 331 - 340   2004年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:GENETICS SOC AM  

    In the course of a large-scale program of ENU mutagenesis, we isolated a dominant mutation, called Velvet. The mutation was found to be uniformly lethal to homozygotes, which do not survive E13.5. Mice heterozygous for the Velvet mutation are born with eyelids open and demonstrate a wavy coat and curly vibrissae. The mutation was mapped to the proximal end of chromosome 11 by genome-wide linkage analysis. On 249 meioses, the locus was confined to a 2.7-Mb region, which included the epidermal growth factor receptor gene (Egfr). An A --&gt; G transition in the Egfr coding region of Velvet mice was identified, causing the amino acid substitution D833G. This substitution alters an essential triad of amino acids (DFG --&gt; GFG) that is normally required for coordination of the ATP substrate. As such, kinase activity is at least mostly abolished, but quaternary structure of the receptor is presumably maintained, accounting for the dominant effect. Velvet is the first known dominant representative of the Egfr allelic series that is fully viable, a fact that makes it particularly useful for developmental studies.

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  • The nonsense allele oblivious reveals a sensor of di-acylglycerides acting in conjunction with TLR2 and TLR6. 査読

    Hoebe K, Tabeta K, Georgel P, Du X, Mudd S, Sovath S, Shamel L, Hartung T, Zähringer U, Beutler B

    Arthritis Research & Therapy   2004年

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  • Lps2 and signal transduction in sepsis: At the intersection of host responses to bacteria and viruses 査読

    B Beutler, K Hoebe, Du, X, E Janssen, P Georgel, K Tabeta

    SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES35 ( 9 ) 563 - 567   2003年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS AS  

    A phenotype-driven approach led to the first understanding of precisely what the Toll-like receptors (TLR) did, when it was determined that the mammalian endotoxin (lipopolysaccharide; LPS) receptor is encoded by TLR4. The TLRs are the primary sensors of the innate immune system, and without them, small inocula of microorganisms pose a major threat to the host, growing unchecked for a long period before they are recognized. Mutations that affect innate immune sensing may account for a substantial fraction of sepsis, and a highly significant excess of mutations in TLR4 has been identified in patients with systemic meningococcal disease. As such, it is important to understand the pathways that are responsible for innate immune sensing, including the signaling intermediates utilized by the TLRs. Random germline mutagenesis identified a locus, Lps2 , which is required for normal responses to double-stranded RNA and LPS. Hence, a single transducer was found to serve both the TLR3 and TLR4 response pathways. The Lps2 mutation was found to ablate entirely the MyD88-independent pathway for LPS sensing, indicating that two and only two branches of the LPS sensing pathway exist in macrophages, and homozygotes for the mutation were resistant to LPS, but markedly susceptible to infection with mouse cytomegalovirus. Remarkably, Lps2 mutant mice entirely failed to produce type I interferons in response to a viral infection. It would appear that Lps2 is the most proximal component of a signal integration system required for innate immune responses to both viral and bacterial diseases. Positional cloning revealed that the TIR adapter protein Trif/Ticam-1 is structurally altered by the Lps2 mutation. This adapter is responsible for shared effects of responses to viral and bacterial pathogens.

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  • Identification of Lps2 as a key transducer of MyD88-independent TIR signalling 査読

    K Hoebe, Du, X, P Georgel, E Janssen, K Tabeta, SO Kim, J Goode, P Lin, N Mann, S Mudd, K Crozat, S Sovath, J Han, B Beutler

    NATURE424 ( 6950 ) 743 - 748   2003年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    In humans, ten Toll-like receptor (TLR) paralogues sense molecular components of microbes, initiating the production of cytokine mediators that create the inflammatory response. Using N-ethyl-N-nitrosourea, we induced a germline mutation called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer. Here we identify the Lps2 mutation: a distal frameshift error in a Toll/interleukin-1 receptor/resistance (TIR) adaptor protein known as Trif or Ticam-1. Trif Lps2 homozygotes are markedly resistant to the toxic effects of LPS, and are hypersusceptible to mouse cytomegalovirus, failing to produce type I interferons when infected. Compound homozygosity for mutations at Trif and MyD88 (a cytoplasmic TIR-domain-containing adaptor protein) loci ablates all responses to LPS, indicating that only two signalling pathways emanate from the LPS receptor. However, a Trif-independent cell population is detectable when Trif Lps2 mutant macrophages are stimulated with LPS. This reveals that an alternative MyD88-dependent 'adaptor X' pathway is present in some, but not all, macrophages, and implies afferent immune specialization.

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  • Single-nucleotide polymorphism in the CD14 promoter and periodontal disease expression in a Japanese population 査読

    K Yamazaki, K Ueki-Maruyama, T Oda, K Tabeta, Y Shimada, H Tai, T Nakajima, H Yoshie, D Herawati, GJ Seymour

    JOURNAL OF DENTAL RESEARCH82 ( 8 ) 612 - 616   2003年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

    It has been reported that there is a relationship between a single-nucleotide polymorphism (SNP) in the promoter region of the CD 14 gene at position -159 (C--&gt;T) and infectious diseases. The aim of the present study was to test the hypthesis that expression of this SNP correlates with periodontal disease in a Japanese population. The CD14 genotype was determined in 163 subjects with periodontitis and in 104 age- and gender-matched control subjects without periodontitis. The genotype distribution and allele frequency within the periodontitis patients were not significantly different from those of control subjects. There was, however, a significant difference in the genotype distribution between young patients (&lt; 35 yrs) and older patients (greater than or equal to 35 yrs). These findings suggest that CD14-159C/T polymorphism is not related to the development of periodontitis in a Japanese population, but that, within the periodontitis subjects, expression of the SNP may be related to early disease activity.

    DOI: 10.1177/154405910308200808

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  • 動脈硬化症におけるPorphyromonas gingivalis GroELに対する免疫応答の解析

    多部田 康一, 山崎 和久, 大澤 豊, 伊藤 晴江, 植木 薫, 斉藤 了, 小熊 文昭, 小玉 誠, 相澤 義房, 吉江 弘正

    BACTERIAL ADHERENCE & BIOFILM15   31 - 38   2002年6月

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    記述言語:日本語   出版者・発行元:日本バイオフィルム学会  

    動脈硬化症患者7名より動脈硬化組織,末梢血を採取し,歯周疾患と動脈硬化症の両疾患に関与すると報告されている60kDa heat shock protein(hsp60)とPorphyromonas gingivalis(Pg)のヒトhspホモローグであるGroELに対する動脈硬化患者における免疫応答について検索した.検討した7名中1名を除いて,PgまたはA.actinomycetemcomitans GroELとhsp60において反応する抗体産生が認められた.さらに分析結果より,歯周炎と動脈硬化症の疫学的因果関係を裏付ける可能性も考えられた

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  • Accumulation of human heat shock protein 60-reactive T cells in the gingival tissues of periodontitis patients 査読

    K Yamazaki, Y Ohsawa, K Tabeta, H Ito, K Ueki, T Oda, H Yoshie, GJ Seymour

    INFECTION AND IMMUNITY70 ( 5 ) 2492 - 2501   2002年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC MICROBIOLOGY  

    Heat shock protein 60s (hsp60) are remarkably immunogenic, and both T-cell and antibody responses to hsp60 have been reported in various inflammatory conditions. To clarify the role of hsp60 in T-cell responses in periodontitis, we examined the proliferative response of peripheral blood mononuclear cells (PBMC), as well as the cytokine profile and T-cell clonality, for periodontitis patients and controls following stimulation with recombinant human hsp60 and Porphyromonas gingivalis GroEL. To confirm the infiltration of hsp60-reactive T-cell clones into periodontitis lesions, nucleotide sequences within complementarity-determining region 3 of the T-cell receptor (TCR) beta-chain were compared between hsp60-reactive peripheral blood T cells and periodontitis lesion-infiltrating T cells. Periodontitis patients demonstrated significantly higher proliferative responses of PBMC to human hsp60, but not to P. gingivalis GroEL, than control subjects. The response was inhibited by anti-major histocompatibility complex class 11 antibodies. Analysis of the nucleotide sequences of the TCR demonstrated that human hsp60-reactive T-cell clones and periodontitis lesion-infiltrating T cells have the same receptors, suggesting that hsp60-reactive T cells accumulate in periodontitis lesions. Analysis of the cytokine profile demonstrated that hsp60-reactive PBMC produced significant levels of gamma interferon (IFN-gamma) in periodontitis patients, whereas P. gingivalis GroEL did not induce any, skewing toward a type1 or type2 cytokine profile. In control subjects no significant expression of IFN-gamma or interleukin 4 was induced. These results suggest that periodontitis patients have human hsp60-reactive T cells with a type I cytokine profile in their peripheral blood T-cell pools.

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  • Self-heat shock protein 60 induces tumour necrosis factor-alpha in monocyte-derived macrophage: possible role in chronic inflammatory periodontal disease 査読

    K Ueki, K Tabeta, H Yoshie, K Yamazaki

    CLINICAL AND EXPERIMENTAL IMMUNOLOGY127 ( 1 ) 72 - 77   2002年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING LTD  

    Heat shock protein 60 (hsp60) has been increasingly recognized as an important molecule in infectious and autoimmune diseases. We have demonstrated previously that serum antibodies to both human hsp60 and Porphyromonas gingivalis GroEL were elevated in periodontitis patients compared with healthy subjects. In order to clarify the relative importance of hsp60 in the inflammatory response in periodontal disease, the stimulatory effect of human and bacterial hsp60 on the production of tumour necrosis factor-alpha (TNF-alpha) was examined in phorbol myristate acetate (PMA)-stimulated THP-1 cells. As bacterial hsp60s, recombinant P. gingivalis and Actinobacillus actinomycetemcomitans GroEL was used. Human hsp60 but not P. gingivalis or A. actinomycetemcomitans GroEL demonstrated stimulatory activity similar to lipopolysaccharide (LPS) derived from the bacteria. The activity of hsp60 was inhibited by anti-CD14 and anti-Toll-like receptor 4 (TLR4) antibodies, suggesting that both CD14 and TLR4 mediate hsp60 signalling. Immunohistochemical analysis demonstrated that hsp60 is abundantly expressed in periodontitis lesions. Therefore, it is postulated that periodontopathic bacteria stimulate the cells in the periodontium to up-regulate the expression of hsp60, which in turn may stimulate macrophage and possibly other cells to produce proinflammatory cytokines. These mechanisms may be involved in the chronicity and tissue destruction of periodontal disease.

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  • Analysis of single nucleotide polymorphisms in the 5'-flanking region of tumor necrosis factor-alpha gene in Japanese patients with early-onset periodontitis 査読

    M Endo, H Tai, K Tabeta, T Kobayashi, K Yamazaki, H Yoshie

    JOURNAL OF PERIODONTOLOGY72 ( 11 ) 1554 - 1559   2001年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ACAD PERIODONTOLOGY  

    Background: Early-onset periodontitis (EOP) is considered to have a genetic basis, which has not been clearly defined. The tumor necrosis factor-alpha (TNF-alpha) gene polymorphism as one of the genetic factors may influence the expression of several chronic inflammatory diseases. The aim of the present study was to evaluate whether the polymorphisms in the 5'-flanking region of the TNF-alpha gene are associated with Japanese EOP patients.
    Methods: Forty-six Japanese, generalized EOP (G-EOP) patients and 104 Japanese healthy subjects were identified according to established clinical criteria. Twenty healthy subjects were analyzed by nucleotide sequence to screen polymorphisms of the 5'-flanking region of the TNF-alpha gene. Then, all subjects were analyzed by polymerase chain reaction and sequencespecific oligonucleotide probe (SSOP) methods.
    Results: We determined 5 single nucleotide polymorphisms at positions - 1031 (T/C), -863 (C/A), -857 (C/T), -308 (G/A), and -238 (G/A) in the 5'-flanking region of the TNF-alpha gene. There were no significant differences in the genotype and allele frequency when we compared G-EOP patients to healthy subjects. Because the frequency of polymorphic alleles at positions -308 and -238 was very low in this study population, we demonstrated the existence of 4 detected haplotypes and 6 detected genotypes concerning 3 single nucleotide polymorphisms (-1031, -863, and -857). The frequency of the H1/H3 (TCC/TCT)-detected genotype tended to decrease in G-EOP patients compared to healthy subjects, but was not statistically significant.
    Conclusion: These findings suggest there is no significant association between polymorphisms in the 5'-flanking region of the TNF-alpha gene and susceptibility to G-EOP in Japanese patients.

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  • Characterization of serum antibody to Actinobacillus actinomycetemcomitans GroEL-like protein in periodontitis patients and healthy subjects 査読

    K Tabeta, H Yoshie, K Yamazaki

    ORAL MICROBIOLOGY AND IMMUNOLOGY16 ( 5 ) 290 - 295   2001年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MUNKSGAARD INT PUBL LTD  

    Recent evidence suggests that molecular mimicry between bacterial and human heat shock protein 60 (hsp60) is involved in various conditions of autoimmune and infectious diseases. Many periodontopathic bacteria have been reported to express GroEL-like protein that is homologous to human hsp60. In this study, the presence of antibodies to the hsp60 of Actinobacillus actinomycetemcomitans in the sera of periodontitis patients and periodontally healthy control subjects was evaluated by enzyme-linked immunosorbent assay using a recombinant A. actinomycetemcomitans GroEL as an antigen. Furthermore, their crossreactivity with Escherichia coli GroEL and Mycobacterium bovis BCG hsp65 was examined. The mean values of antibody were 0.624 (range 0.088-1.113) and 0.728 (range 0.217-1.296) in control subjects and periodontitis patients, respectively. The antibody levels to A. actinomycetemcomitans after absorption with E. coli GroEL and M. bovis BCG clearly decreased in both control subjects and periodontitis patients. The remaining antibody levels to A. actinomycetemitan. tans GroEL after absorption with M. bovis BCG hsp65 were higher than those with E. coli GroEL, indicating higher cross-reactivity with E. coli GroEL. These results suggest that not only periodontitis patients but also periodontally healthy subjects may be infected with A. actinomycetemcomitans but that the part of the antibody could be derived from the cross-reactivity with E. coli GroEL ny relationship of the antibody to the disease, however, remains to be determined.

    DOI: 10.1034/j.1399-302X.2001.016005290.x

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  • Interleukin-10 gene promoter polymorphism in Japanese patients with adult and earlyonset periodontitis 査読

    K Yamazaki, K Tabeta, T Nakajima, Y Ohsawa, K Ueki, H Itoh, H Yoshie

    JOURNAL OF CLINICAL PERIODONTOLOGY28 ( 9 ) 828 - 832   2001年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MUNKSGAARD INT PUBL LTD  

    Background: IL-10 is an anti-inflammatory cytokine, which may modulate disease expression in chronic inflammatory periodontal disease. 3 dimorphic polymorphisms within the IL-10 gene promoter have recently been identified and appear to influence regulation of its expression.
    Aim: The aim of the present study was to investigate whether the promoter polymorphisms are associated with adult periodontitis (A-P) and generalized early-onset periodontitis (G-EOP). Methods: Genomic DNA was obtained from 34 AP patients, 18 G-EOP patients and 52 controls. The promoter region between - 506 and - 1140 was amplified by polymerase chain reaction, and polymorphisms were detected by nucleotide sequencing.
    Results: The haplotype frequencies in Japanese were quite different from those of Caucasian and were even slightly different from those of southern Chinese with systemic lupus erythematosus. We found no significant difference in allele or haplotype frequencies between patients and controls.
    Conclusions: IL-10 production may be regulated within the complex cytokine network in chronic inflammatory periodontal disease, rather than the gene polymorphisms.

    DOI: 10.1034/j.1600-051x.2001.028009828.x

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    その他リンク: http://orcid.org/0000-0002-7019-1872

  • Toll-like receptors confer responsiveness to lipopolysaccharide from Phorphyromonas gingivalis in human gingival fibroblast 査読

    K Tabeta, K Yamazaki, S Akashi, K Miyake, H Kumada, T Umemoto, H Yoshie

    INFECTION AND IMMUNITY68 ( 6 ) 3731 - 3735   2000年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC MICROBIOLOGY  

    Gingival fibroblasts produce proinflammatory cytokines in response to lipopolysaccharide (LPS) from periodontopathic bacteria. Recently it has become evident that the human homologue of Drosophila Toll can transduce intracellular signaling by LPS stimulation. Toll-like receptors (TLRs) have been identified in myeloid cells; however, their role in nonmyeloid cells such as gingival fibroblasts has not been fully elucidated. Here, we report that human gingival fibroblasts constitutively express TLR2 and TLR4 and that their levels of expression are increased by stimulation with LPS from Porphyromonas gingivalis. Upregulated expression of interleukin-6 gene and protein in fibroblasts stimulated with LPS is inhibited by anti-TLR4 antibody. These findings suggest that TLRs may confer responsiveness to LPS in gingival fibroblasts.

    DOI: 10.1128/IAI.68.6.3731-3735.2000

    DOI: 10.1128/iai.68.6.3731-3735.2000

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  • Elevated humoral immune response to heat shock protein 60 (hsp60) family in periodontitis patients. 査読 国際誌

    K Tabeta, K Yamazaki, H Hotokezaka, H Yoshie, K Hara

    Clinical and experimental immunology120 ( 2 ) 285 - 93   2000年5月

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    記述言語:英語  

    The presence of antibodies to the 60-kD human and Porphyromonas gingivalis GroEL hsp60 in the sera and inflamed gingival tissues of periodontitis patients was examined. In order to obtain the antigens, recombinant plasmids carrying human hsp60 and P. gingivalis GroEL genes were constructed and expressed as histidine-tagged recombinant proteins. Immunoreactivities of these proteins were confirmed by MoAbs specific to mammalian hsp60 and cross-reactive with both mammalian and bacterial hsp60. Western blot analysis clearly demonstrated that the number of periodontitis patients showing a positive response to P. gingivalis GroEL was higher than the number of periodontally healthy subjects. Furthermore, anti-P. gingivalis GroEL antibody was detected in all samples of gingival tissue extracts. For human hsp60, a higher frequency of seropositivity was found in the periodontitis patients than in the healthy subjects. In addition, the periodontitis patients demonstrated stronger reactivity compared with the healthy subjects. Quantitative analysis of serum antibodies by ELISA also demonstrated that the levels of antibodies in the sera of patients were significantly higher than those of control subjects. In the gingival tissue extracts, seven out of 10 patients demonstrated a positive response to human hsp60 and tso of these demonstrated strong positivity. Affinity-purified serum antibodies to human hsp60 and P. gingivalis GroEL from selected patients reacted with P. gingivalis GroEL and human hsp60, respectively, suggesting cross-reactivity of antibodies. These results suggest that molecular mimicry between GroEL of the periodontopathic bacterium P. gingivalis and autologous human hsp60 may play some role in immune mechanisms in periodontitis.

    DOI: 10.1046/j.1365-2249.2000.01216.x

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  • Selective expansion of T cells in gingival lesions of patients with chronic inflammatory periodontal disease 査読

    K Yamazaki, T Nakajima, Y Ohsawa, K Tabeta, H Yoshie, K Sakurai, GJ Seymour

    CLINICAL AND EXPERIMENTAL IMMUNOLOGY120 ( 1 ) 154 - 161   2000年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL SCIENCE LTD  

    Chronic inflammatory periodontal diseases are characterized by a cellular infiltrate and are similar in many respects to other chronic inflammatory diseases. While periodontopathic bacteria have been recognized as the principal causative agent and the immune response to these bacteria is thought to be responsible for the tissue destruction, the full aetiological spectrum is still incompletely understood. In addition to many cell types such as polymorphonuclear leucocytes and macrophages, T cells have been implicated in pathogenesis and are considered to have regulatory roles in progression of the disease. Based on our recent studies demonstrating biased expression of several V beta families in periodontitis tissues, the aim of this study was to characterize further the T cells relevant to the disease process by reverse transcription-polymerase chain reaction-single-strand conformation polymorphism (RT-PCR-SSCP) and subsequent nucleotide sequence analysis of complementarity-determining region 3 (CDR3) of the TCR beta-chain. In spite of the likely involvement of numerous bacteria, the present study has clearly shown the oligoclonality of infiltrating T cells in periodontitis lesions in contrast to low clonality of peripheral blood T cells as evidenced by the appearance of distinct bands in gingival tissue samples and smear pattern of peripheral blood on SSCP gels. These were confirmed by the DNA sequencing of the CDR3 of V beta 16 of selected samples. The analysis of deduced amino acid sequences demonstrated amino acid motifs in the CDR3 region of the periodontitis lesion-derived sequences from each patient. The results indicate that gingival tissue-infiltrating T cells recognizing a limited number of antigens or epitopes are involved in the disease process.

    DOI: 10.1046/j.1365-2249.2000.01179.x

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  • 糖尿病合併症の実態とその抑制に関する大規模観察研究ベースライン時の口腔所見JDCP study 6

    稲垣 幸司, 菊池 毅, 野口 俊英, 三谷 章雄, 成瀬 桂子, 松原 達昭, 川浪 雅光, 根岸 淳, 古市 保志, 根本 英二, 山田 聡, 吉江 弘正, 多部田 康一, 富田 幸代, 齋藤 淳, 片桐 さやか, 和泉 雄一, 新田 浩, 岩田 隆紀, 沼部 幸博, 山本 松男, 吉成 伸夫, 藤田 剛, 栗原 英見, 西村 英紀, 永田 俊彦, 湯本 浩通, 内藤 徹, 野口 和行, 伊藤 公一, 村上 伸也, 西村 理明, 田嶼 尚子, 糖尿病データベース構築委員会

    糖尿病63 ( 4 ) 195 - 205   2020年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

    JDCP studyベースライン時の糖尿病患者6,099名(1型6%,2型94%,61.1±8.1歳)の病態と口腔所見の関係を検討した.現在歯数は平均19.8本,2型糖尿病で男性より女性の方が少なかった.1年間の歯の喪失者,歯肉腫脹既往者,口腔清掃回数2回以上,歯間清掃用具使用者,歯科定期健診者の割合は,それぞれ17%,32%,69%,37%,43%であった.関連9因子を説明変数,現在歯数(20歯未満,20歯以上)を従属変数とした多重ロジスティック回帰分析では,1型糖尿病でHbA1c 7.0%以上になると20歯未満となるオッズ比(OR)は2.38(95%CI 1.25-4.78),2型糖尿病でHbA1c 8.0%以上になると20歯未満となるORは1.16(95%CI 1.00-1.34)となった.糖尿病患者では,現在歯数が少なく血糖コントロール状態の悪化に伴い歯の喪失リスクが高くなった.(著者抄録)

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  • 米由来ペプチドによる炎症制御機構の検索と歯周病治療への応用研究

    田村 光, 前川 知樹, 土門 久哲, 日吉 巧, 米澤 大輔, 前田 健康, 多部田 康一, 寺尾 豊

    新潟歯学会雑誌49 ( 2 ) 82 - 82   2019年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Porphyromonas gingivalisがNASH病態形成に与える影響の解析

    山崎恭子, 山崎恭子, 中島麻由佳, 中島麻由佳, 竹内麻衣, 竹内麻衣, 原(山田)実生, 原(山田)実生, 都野隆博, 都野隆博, 松岸葵, 松岸葵, 松川(松田, 由美, 佐藤圭祐, 高橋直紀, 多部田康一, 山崎和久

    日本歯周病学会会誌(Web)61 ( 春季特別 ) 125 - 125   2019年5月

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  • 腸内細菌の変動が歯周炎の発症・進行に与える影響の解析

    佐藤圭祐, 佐藤圭祐, 松川由実, 原実生, 原実生, 竹内麻衣, 竹内麻衣, 都野隆博, 都野隆博, 松岸葵, 松岸葵, 山崎恭子, 山崎恭子, 多部田康一, 山崎和久

    日本歯周病学会会誌(Web)61 ( 春季特別 ) 124 - 124   2019年5月

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  • エリスロマイシンのDel-1再誘導による炎症性骨吸収抑制効果の検証

    田村 光, 前川 知樹, 土門 久哲, 日吉 巧, 米澤 大輔, 永井 康介, 前田 健康, 寺尾 豊, 多部田 康一

    日本歯周病学会会誌61 ( 春季特別 ) 126 - 126   2019年5月

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  • 口腔細菌の脂質代謝に由来する機能性脂肪酸HYAは歯肉上皮バリア機能を強化することで歯周炎の発症を抑制する

    山田実生, 山田実生, 高橋直紀, 高橋直紀, 松田由実, 佐藤圭祐, 横地麻衣, 横地麻衣, SULIJAYA Benso, SULIJAYA Benso, 多部田康一, 山崎和久

    新潟歯学会雑誌48 ( 2 ) 110‐111 - 111   2018年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • P.gingivalis感染におけるPCSK9産生の誘導機構

    横地麻衣, 横地麻衣, 多部田康一, 高橋直紀, 高橋直紀, 宮澤春菜, 松田由実, 佐藤圭祐, 山田実生, 山田実生, SULIJAYA Benso, SULIJAYA Benso, 山崎和久

    新潟歯学会雑誌48 ( 2 ) 110 - 110   2018年12月

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  • 肺炎球菌性肺炎の病態発症メカニズムの解析と新規肺炎予防法への展開

    永井 康介, 土門 久哲, 前川 知樹, 日吉 巧, 田村 光, 米澤 大輔, 荒井 良明, 横地 麻衣, 多部田 康一, 寺尾 豊

    新潟歯学会雑誌48 ( 1 ) 57 - 58   2018年6月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 食物由来ペプチドを用いた炎症と骨吸収の制御法の検索

    田村光, 田村光, 田村光, 前川知樹, 前川知樹, 米澤大輔, 土門久哲, 土門久哲, 永井康介, 日吉巧, 日吉巧, 多部田康一, 多部田康一, 前田健康, 寺尾豊, 寺尾豊, 吉江弘正

    日本歯周病学会会誌(Web)60   125   2018年5月

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  • 食物由来ペプチドを用いた炎症と骨吸収の制御法の検索

    田村 光, 前川 知樹, 米澤 大輔, 土門 久哲, 永井 康介, 日吉 巧, 多部田 康一, 前田 健康, 寺尾 豊, 吉江 弘正

    日本歯周病学会会誌60 ( 春季特別 ) 125 - 125   2018年5月

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  • Porphyromonas gingivalis口腔投与のコラーゲン誘導性関節炎増悪メカニズムの解析

    佐藤圭祐, 佐藤圭祐, 高橋直紀, 高橋直紀, 中島麻由佳, 中島麻由佳, 松田由実, 松田由実, 山田実生, 山田実生, 横地麻衣, 横地麻衣, 多部田康一, 中島貴子, 山崎和久

    新潟歯学会雑誌46 ( 2 ) 116 - 116   2016年12月

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  • 細菌抗原によるPCSK9産生の誘導機構

    横地麻衣, 横地麻衣, 多部田康一, 宮澤春菜, 野中由香莉, 高橋直紀, 松田由実, 松田由実, 佐藤圭祐, 佐藤圭祐, 山田実生, 山田実生, 伊藤晴江, 中島貴子, 山崎和久

    日本歯科保存学会学術大会プログラムおよび講演抄録集(Web)145th   ROMBUNNO.P94 (WEB ONLY) - 145   2016年10月

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  • 口腔細菌脂質代謝に由来する機能性脂肪酸HYAは歯肉上皮バリア機能の低下を抑制する

    山田実生, 山田実生, 高橋直紀, 高橋直紀, 高橋直紀, 松田由実, 松田由実, 佐藤圭祐, 佐藤圭祐, 横地麻衣, 横地麻衣, 多部田康一, 多部田康一, 中島貴子, 山崎和久

    日本歯周病学会会誌(Web)58   112   2016年9月

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  • カプサイシン受容体TRPV1の活性化が歯槽骨吸収におよぼす影響

    高橋直紀, 高橋直紀, 松田由実, 松田由実, 佐藤圭祐, 佐藤圭祐, 多部田康一, 山崎和久, 前田健康

    日本歯周病学会会誌(Web)58   124   2016年9月

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  • 実験的歯周炎モデルマウスの歯槽骨吸収におけるTRPV1チャネルタンパクの関与

    高橋直紀, 松田由実, 佐藤圭祐, 多部田康一, 前田健康, 山崎和久

    日本歯科医師会雑誌69 ( 5 ) 487   2016年8月

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  • 結紮誘導歯周炎モデルマウスにおける全身への影響とそのメカニズムの解析

    松田由実, 松田由実, 高橋直紀, 高橋直紀, 中島麻由佳, 中島麻由佳, 佐藤圭祐, 佐藤圭祐, 多部田康一, 中島貴子, 山崎和久

    新潟歯学会雑誌46 ( 1 ) 48 - 48   2016年7月

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  • TRPV1受容体の活性化は神経ペプチド産生を介して歯槽骨吸収を抑制する

    高橋直紀, 高橋直紀, 高橋直紀, 松田由実, 松田由実, 佐藤圭祐, 佐藤圭祐, 多部田康一, 吉江弘正, 山崎和久

    日本歯科保存学会学術大会プログラムおよび講演抄録集(Web)144th   P7 (WEB ONLY) - 65   2016年6月

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  • 外傷性咬合により誘導される歯槽骨吸収に対するResveratrolの影響

    松田由実, 松田由実, 皆川高嘉, 皆川高嘉, 高橋直紀, 高橋直紀, 佐藤圭祐, 佐藤圭祐, 横地麻衣, 横地麻衣, 山田実生, 山田実生, 多部田康一, 中島貴子, 山崎和久

    日本歯科保存学会学術大会プログラムおよび講演抄録集(Web)144th   A7 (WEB ONLY) - 27   2016年6月

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  • Porphyromonas gingivalis口腔投与のコラーゲン誘導性関節炎増悪メカニズムの解析

    佐藤圭祐, 佐藤圭祐, 高橋直紀, 高橋直紀, 中島麻由佳, 中島麻由佳, 松田由実, 松田由実, 山田実生, 山田実生, 横地麻衣, 横地麻衣, 多部田康一, 中島貴子, 山崎和久

    日本歯周病学会会誌(Web)58 ( 春季特別 ) 116 - 116   2016年4月

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  • 歯周炎と血液・尿中バイオロジカルマーカーとの関連解析

    中島麻由佳, 中島麻由佳, 多部田康一, 宮内小百合, 杉田典子, 小松康高, 本田朋之, 高橋直紀, 宮澤春菜, 有松圭, 皆川高嘉, 松田由実, 松田由実, 佐藤圭祐, 佐藤圭祐, 山崎和久, 吉江弘正

    日本歯科保存学会学術大会プログラムおよび講演抄録集(Web)143rd   P126 (WEB ONLY) - 197   2015年11月

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  • 歯周組織局所の炎症およびP.gingivalisによる腸内細菌叢の変動が全身に及ぼす影響とその分子機構の比較

    松田由実, 松田由実, 高橋直紀, 高橋直紀, 有松圭, 有松圭, 中島麻由佳, 中島麻由佳, 佐藤圭祐, 佐藤圭祐, 多部田康一, 中島貴子, 山崎和久

    日本歯周病学会会誌(Web)57 ( 秋季特別 ) 129 - 129   2015年8月

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  • Porphyromonas gingivalis経口単回投与によるマウス腸内細菌叢の変動

    中島麻由佳, 中島麻由佳, 有松圭, 有松圭, 高橋直紀, 高橋直紀, 皆川高嘉, 皆川高嘉, 松田由実, 松田由実, 佐藤圭祐, 佐藤圭祐, 中島貴子, 多部田康一, 山崎和久

    新潟歯学会雑誌45 ( 1 ) 26 - 27   2015年6月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

    J-GLOBAL

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  • 歯周炎モデルマウスにおける腸内細菌叢の変動と免疫応答への影響

    高橋直紀, 有松圭, 中島麻由佳, 松田由実, 佐藤圭祐, 多部田康一, 中島貴子, 加藤完, 大野博司, 山崎和久

    腸内細菌学雑誌29 ( 2 ) 91 - 91   2015年4月

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    記述言語:日本語   出版者・発行元:(公財)日本ビフィズス菌センター  

    J-GLOBAL

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  • Porphyromonas gingivalis経口単回投与によるマウス腸内細菌叢の変動

    中島麻由佳, 有松圭, 高橋直紀, 皆川高嘉, 山田ひとみ, 松田由実, 佐藤圭祐, 多部田康一, 中島貴子, 山崎和久

    日本歯科保存学会学術大会プログラムおよび講演抄録集(Web)141st   B24 (WEB ONLY) - 62   2014年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本歯科保存学会  

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  • Current evidence and biological plausibility linking periodontitis to atherosclerotic cardiovascular disease

    Koichi Tabeta, Hiromasa Yoshie, Kazuhisa Yamazaki

    Japanese Dental Science Review50 ( 3 ) 55 - 62   2014年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:Elsevier Ltd  

    The relationship between poor oral health and systemic diseases has been increasingly recognized over the past two decades. Atherosclerosis is an important basal component of atherosclerotic cardiovascular disease (ACVD), which is the primary cause of death worldwide, including Japan. The accumulation of multiple individual epidemiological studies has paved the way for subsequent systematic reviews that have demonstrated that periodontitis can be considered as an emerging risk factor for ACVD. Although the causal mechanisms by which periodontitis accelerates ACVD have not been fully elucidated, plausible evidence regarding the inflammatory response due to inflammatory mediators and bacterial etiologies, and the recognition of altered lipid metabolism in patients with periodontitis suggest that infection with periodontopathic bacteria can influence atherogenesis in vitro and in vivo. Animal model studies have strengthened this evidence. However, there have been a lack of interventional studies that show the effects of periodontal treatment on the future risk of ACVD
    this lack of evidence critically weakens the importance of the relationship between the two diseases. This review presents a summary of the current evidence and biological plausibility that link periodontitis to ACVD. © 2014 Japanese Association for Dental Science.

    DOI: 10.1016/j.jdsr.2014.03.001

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  • THE EFFECTS OF NKT CELLS ON ATHEROGENESIS IN PORPHYROMONAS GINGIVALIS INFECTION MODEL

    T. Nakajima, Y. Aoki, H. Miyashita, S. Miyauchi, H. Miyazawa, K. Tabeta, K. Yamazaki

    INFLAMMATION RESEARCH60   220 - 220   2011年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:BIRKHAUSER VERLAG AG  

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  • Periodontitis as a risk factor for atherosclerosis

    Kazuhisa Yamazaki, Koichi Tabeta, Takako Nakajima

    Journal of Oral Biosciences53 ( 3 ) 221 - 232   2011年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:Japanese Association for Oral Biology  

    The relationship between poor oral health and systemic diseases has been increasingly recognized over the past two decades. Recent studies have suggested that periodontal disease caused by perio-dontopathic bacteria increases the risk of atherothrombotic disease. Atherosclerosis is an important component of coronary heart disease (CHD), which is the leading cause of death worldwide, including in Japan. Recent evidence has suggested that chronic inflammation plays a key role in promoting or accelerating atherosclerosis. Thus, periodontal disease has drawn considerable attention, and a number of epidemiologi-cal studies have shown that an association between the two diseases is highly likely. Several biologically plausible mechanisms have been presented to explain the association, such as bacteremia, elevated levels of inflammatory markers and the generation of cross-reactive immune responses by chronic infections. There is evidence demonstrating the direct invasion of periodontopathic bacteria into host cells, increased levels of high-sensitivity C-reactive protein and elevated levels of cross-reactive antibody between human heat-shock protein 60 and GroEL of Porphyromonas gingivalis. In addition, several animal studies aimed at clarifying the effect of periodontopathic bacterial infection on atherogenesis have successfully shown the formation of atheromatous plaque and the elevation of systemic inflammatory markers. This review presents an update of the current understanding of the contribution of poor oral health to systemic diseases and discusses the possible mechanisms involved.

    DOI: 10.2330/joralbiosci.53.221

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  • 新たな視点から口腔疾患を誘因とする難治性疾患を考える 歯周疾患の動脈硬化症リスクに及ぼす影響

    山崎 和久, 多部田 康一, 前川 知樹, 高橋 直紀, 青木 由香莉, 宮下 博考, 宮内 小百合, 米澤 大輔, 本田 朋之, 奥井 隆文, 奥井 桂子, 伊藤 晴江, 中島 貴子

    Journal of Oral Biosciences52 ( Suppl ) 67 - 67   2010年9月

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    記述言語:日本語   出版者・発行元:(一社)歯科基礎医学会  

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  • 新たな骨形成不全症モデルマウスに見られた選択的スプライシング sealにおけるGT-AGルールの例外

    多部田 康一, 高橋 直紀, 前川 知樹, 山崎 和久, 網塚 憲生

    新潟歯学会雑誌40 ( 1 ) 79 - 81   2010年6月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 歯周炎患者におけるPorphyromonas gingivalisに対する抗体価と高感度CRPの関連性

    宮下 博考, 米澤 大輔, 本田 朋之, 奥井 隆文, 奥井 桂子, 前川 知樹, 高橋 直紀, 伊藤 晴江, 中島 貴子, 多部田 康一, 山崎 和久

    新潟歯学会雑誌40 ( 1 ) 98 - 98   2010年6月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Unc93 homolog B1 regulates the balance of toll-like receptor 7 and toll-like receptor 9 responses reciprocally in dendritic cells 査読

    Ryutaro Fukui, Shin-ichiroh Saitoh, Fumi Matsumoto, Hiroko Kozuka-Hata, Masaaki Oyama, Koichi Tabeta, Bruce Beutler, Kensuke Miyake

    CYTOKINE48 ( 1-2 ) 26 - 26   2009年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.cyto.2009.07.102

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  • 歯周炎患者におけるPorphyromonas gingivalisに対する抗体価と高感度CRPの関連性

    宮下 博考, 米澤 大輔, 本田 朋之, 奥井 隆文, 奥井 桂子[梶田], 前川 知樹, 高橋 直紀, 伊藤 晴江, 中島 貴子, 多部田 康一, 山崎 和久

    日本歯周病学会会誌51 ( 秋季特別 ) 99 - 99   2009年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本歯周病学会  

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  • ORAL INFECTION OF PORPHYROMONAS GINGIVALIS INDUCES PRO-ATHEROGENIC CHANGE IN MICE

    K. Yamazaki, T. Maekawa, N. Takahashi, T. Nakajima, K. Tabeta

    ATHEROSCLEROSIS SUPPLEMENTS10 ( 2 )   2009年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

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  • 歯周炎の病態は冠動脈血管内皮細胞のEarly growth response-1発現を上昇・誘導し炎症反応を促進させる

    前川 知樹, 高橋 直紀, 本田 朋之, 宮下 博孝, 米澤 大輔, 奥井 隆文, 多部田 康一, 山崎 和久

    新潟歯学会雑誌39 ( 1 ) 86 - 86   2009年6月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Porphyromonas gingivalis感染が冠動脈疾患リスクに及ぼす影響 基本健康診査受診者における解析

    米澤 大輔, 宮下 博孝, 前川 知樹, 高橋 直紀, 青木 由香莉, 奥井 隆文, 中島 貴子, 田辺 直仁, 多部田 康一, 山崎 和久

    新潟歯学会雑誌39 ( 1 ) 87 - 87   2009年6月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Porphyromonas gingivalis感染が冠動脈疾患リスクに及ぼす影響 基本健康診査受診者における解析

    米澤 大輔, 宮下 博考, 前川 知樹, 高橋 直紀, 青木 由香莉, 奥井 隆文, 中島 貴子, 田辺 直仁, 多部田 康一, 山崎 和久

    日本歯周病学会会誌51 ( 春季特別 ) 127 - 127   2009年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本歯周病学会  

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  • 歯周炎が血清中の動脈硬化関連炎症マーカーに及ぼす影響

    中島 貴子, 本田 朋之, 奥井 隆文, 梶田 桂子, 土門 久哲, 伊藤 晴江, 多部田 康一, 山崎 和久

    日本歯周病学会会誌50 ( 秋季特別 ) 123 - 123   2008年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本歯周病学会  

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  • 歯周炎の病態とSelenoprotein S遺伝子多型の関連

    山崎 和久, 本田 朋之, 天沼 亮子, 梶田 桂子, 奥井 隆文, 土門 久哲, 吉江 弘正, 多部田 康一, 中島 貴子, 山田 聡, 村上 伸也

    日本歯周病学会会誌49 ( 春季特別 ) 129 - 129   2007年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本歯周病学会  

    DOI: 10.14833/amjsp.2007s.0.61.0

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  • 歯周炎の病態とSelenoprotein S遺伝子多型の関連

    山崎 和久, 山田 聡, 村上 伸也, 本田 朋之, 天沼 亮子, 梶田 桂子, 奥井 隆文, 土門 久哲, 吉江 弘正, 多部田 康一, 中島 貴子

    特定非営利活動法人 日本歯周病学会学術大会 プログラムおよび講演抄録集2007 ( 0 ) 61 - 61   2007年

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本歯周病学会  

    DOI: 10.14833/amjsp.2007s.0.61.0

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  • マイクロサテライトを用いた相関解析による歯周病感受性遺伝子同定 : 第19染色体全長の解析

    田井 秀明, 島田 靖子, 小林 哲夫, 多部田 康一, 山崎 和久, 石原 裕一, 野口 俊英, 曽我 賢彦, 高柴 正悟, 小林 輝一, 岡 晃, 猪子 英俊, 吉江 弘正

    日本歯科保存学雑誌 = THE JAPANESE JOURNAL OF CONSERVATIVE DENTISTRY48   2005年10月

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    記述言語:日本語  

    CiNii Article

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  • 3D, a novel mutation that confers defective sensing by toll-like receptors 3, 7 and 9.

    K Tabeta, Du, X, G Philippe, K Hoebe, N Mann, S Mudd, N Huser, L Shamel, K Crozat, L Tarantino, M Cooke, B Beutler

    BLOOD104 ( 11 ) 938A - 938A   2004年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

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  • Pinkie, the first viable germline hypomorph allele of retinoid X receptor alpha, reveals an important role for RXRa in Th2 development.

    Du, X, T Bigby, K Tabeta, E Janssen, K Crozat, M Navjiwan, B Beutler

    BLOOD104 ( 11 ) 93A - 93A   2004年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

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  • Self-hsp60 induces tumor necrosis factor-a in monocyte-derived macrophage.

    K Ueki, K Tabeta, H Yoshie, K Yamazaki

    JOURNAL OF DENTAL RESEARCH81   A124 - A124   2002年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

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  • Expression of Toll-like receptor 2 and 4 in human gingival fibroblasts

    K Tabeta, H Yoshie, K Yamazaki

    JOURNAL OF DENTAL RESEARCH79   487 - 487   2000年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC DENTAL RESEARCH  

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  • Reduction of the invariant V alpha 24J alpha Q-bearing T cells in periodontitis lesion

    Y Ohsawa, T Nakajima, K Tabeta, H Yoshie, K Yamazaki

    JOURNAL OF DENTAL RESEARCH79   486 - 486   2000年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC DENTAL RESEARCH  

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  • Accumulation of T cells specific to human hsp60 in periodontitis lesions.

    K Yamazaki, T Nakajima, K Tabeta, Y Ohsawa, T Aoyagi, H Yoshie

    JOURNAL OF DENTAL RESEARCH79   486 - 486   2000年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC DENTAL RESEARCH  

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▶ 全件表示

受賞

  • 日本歯科保存学会奨励賞

    2002年  

    多部田 康一

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  • 財団法人上原記念生命科学財団 リサーチフェローシップ

    2002年  

    多部田 康一

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  • 日本歯周病学会奨励賞

    2002年  

    多部田 康一

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共同研究・競争的資金等の研究

  • Therapeutic biofilmによる歯周病・根面う蝕治療アプローチの転換

    研究課題/領域番号:19K22705  2019年06月 - 2021年03月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    多部田 康一, 野中 由香莉, 寺尾 豊, 藤本 啓二, 高橋 直紀

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

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  • フレイルとAMRの課題に対応する食品由来機能ペプチドを素材とした歯周病医薬開発

    研究課題/領域番号:19H03829  2019年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    多部田 康一, 谷口 正之, 野中 由香莉, 寺尾 豊, 藤本 啓二, 高橋 直紀

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

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  • 口腔-腸管連関の新展開:嚥下された歯周病原細菌は腸炎を悪化させるか?

    研究課題/領域番号:19K10126  2019年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    高橋 直紀, 多部田 康一, 片倉 響子

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 歯周炎病態形成におけるTRPチャネルを介した神経-骨代謝ネットワークの解明

    研究課題/領域番号:16K11827  2016年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    高橋 直紀, 多部田 康一, 山崎 和久

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    歯周炎は歯槽骨の吸収を特徴とする慢性炎症性疾患であり,主要な歯の喪失原因である.近年同定されたTRPV1タンパクは,様々な炎症性疾患に関与することが知られているが,歯周炎への関与はほとんど報告がない.実験的歯周炎モデルマウスにおいて,TRPV1ノックアウトマウスは歯槽骨破壊が亢進することが確認された.そのメカニズムとして,TRPV1の活性化によって産生誘導される神経ペプチドCGRPが破骨細胞分化を抑制することが示唆された.TRPV1アゴニストであるカプサイシンを実験的歯周炎モデルマウスに投与することで歯周炎が抑制された.以上より,TRPV1が歯周炎の病態形成に関与することが示唆された.

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  • コメ由来ペプチド素材を用いた口腔ケアアプリケーションと歯周病ペプチド医薬の開発

    研究課題/領域番号:16K15845  2016年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    多部田 康一, 谷口 正之

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    配分額:3380000円 ( 直接経費:2600000円 、 間接経費:780000円 )

    本研究においては,コメαアミラーゼ由来のAmyΙ-1-18ペプチドに着目し,歯周病に対する抑制能とその作用機序を明らかにすることを目的とした.AmyΙ-1-18ペプチドは,炎症性サイトカイン産生の抑制を介してマウス歯周炎モデルにおいて歯槽骨吸収を阻害した. さらに,AmyΙ-1-18ペプチドは,マクロファージにおいてLPSおよびIL-1βによって誘導される炎症性サイトカインを抑制した. AmyΙ-1-18ペプチドは抗炎症性作用によって,歯周病を抑制することが明らかとなった.この研究の成果により,新規歯周病医薬開発の基礎となるデータが得られた.

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―(国際共同研究強化)

    研究課題/領域番号:15KK0338  2016年 - 2018年

    日本学術振興会  科学研究費助成事業 国際共同研究加速基金(国際共同研究強化)  国際共同研究加速基金(国際共同研究強化)

    多部田 康一

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    配分額:14560000円 ( 直接経費:11200000円 、 間接経費:3360000円 )

    唾液中の免疫グロブリン(分泌型IgA抗体)は歯周病などの口腔感染症の予防に役割を果たす。この分泌型IgAを効果的に誘導することは歯周病の予防・治療における一つのアプローチである。本研究においては,ENUマウスミュータジェネシスと呼ばれるマウス遺伝子変異体の遺伝子機能の違いを検出する研究手法により分泌型IgAの産生を制御する遺伝子の検索を行った。その結果,唾液中分泌型IgA量に影響を与える遺伝子変異(Yummy)を検出した。Yummyミューテーションを持つ責任遺伝子のノックアウトマウスが作成された。今後の遺伝子機能解析が予定される。

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  • 歯周炎病態形成におけるTRPチャネルを介した神経-骨代謝ネットワークの解明

    2016年 - 2018年

    科学研究費  基盤研究(C) 

    高橋直紀

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    資金種別:競争的資金

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  • コメ由来ペプチド素材を用いた口腔ケアアプリケーションと歯周病ペプチド医薬の開発

    2016年 - 2018年

    科学研究費  挑戦的萌芽研究 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―

    研究課題/領域番号:15H05052  2015年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    多部田 康一, 寺尾 豊, 高橋 直紀, 山崎 和久

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

    感染症である歯周炎におけるワクチンの有効性は示唆されているが、実際に応用可能なワクチンの開発にはこれまで至っていない。本研究において、粘膜免疫における分泌型IgA産生誘導を焦点に歯周炎ワクチン開発の可能性を検証した。その結果、核酸抗原様化合物であるイミダゾキノリン誘導体を介してケモカイン産生および濾胞性T細胞活性化が誘導され、分泌型IgA産生が促進された。これらのことから、核酸抗原をアジュバンドとした歯周炎ワクチン開発の可能性が示唆された。

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―(国際共同研究強化)

    2015年 - 2018年

    科学研究費  国際共同研究加速基金(国際共同研究強化) 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―

    2015年 - 2017年

    科学研究費  基盤研究(B) 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • IL-10応答を中心とした歯周病原細菌感染に対する慢性炎症成立機構の基盤解明

    研究課題/領域番号:25463216  2013年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    中島 貴子, 多部田 康一, 伊藤 晴江, 山崎 和久, 山田 ひとみ, 松田 由実

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    抗炎症性サイトカインIL-10を中心とした歯周炎の発症・進行抑制に対する効果を検討した。ヒト歯周炎患者の歯肉病変部では歯肉炎に比較してIL-10が有意に高いレベルで検出された。マウス絹糸結紮歯周炎モデルにおいて、口腔細菌の増加、歯肉の著明な炎症、歯槽骨吸収と同時に、歯肉でのIL-10発現の上昇を認めた。このモデルにおいて歯肉局所にIL-10を直接投与すると炎症、骨吸収の抑制作用は認められなかったが、腹腔投与すると歯肉の炎症性サイトカインは抑制しないが歯槽骨吸収は抑制傾向が認められた。歯周炎の骨吸収は局所の炎症のみでなく、全身性に制御されていることが示唆された。

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  • IL-10応答を中心とした歯周病原細菌感染に対する慢性炎症成立機構の基盤解明

    2013年 - 2015年

    科学研究費  基盤研究(C) 

    中島貴子

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    資金種別:競争的資金

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  • 加齢により減少する新規細胞外マトリクスの機能解析-組織再生応用への新たな可能性-

    2012年

    新潟大学  新潟大学 プロジェクト 推進経費 ・奨励研究 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 脂質代謝バランスの揺らぎと歯周疾患のパスウェイ解析

    研究課題/領域番号:23390476  2011年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    山崎 和久, 多部田 康一, 中島 貴子, 土門 久哲, 中山 浩次

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    配分額:19110000円 ( 直接経費:14700000円 、 間接経費:4410000円 )

    本研究課題では歯周病原細菌感染の脂質代謝への影響を解析した。その結果、歯周炎患者において脂質プロフィールが動脈硬化性に変化しているとともに、血中LDLコレステロールの制御に重要なPCSK9が上昇していることが明らかになった。また、マウス実験的歯周炎モデルにおいては、PCSK9をはじめとする脂質代謝制御に関連する遺伝子発現が動脈硬化性に変化するとともに、HDLコレステロールの低下が認められた。これらより、歯周病原細菌感染はコレステロールの排出抑制、LDL受容体の発現上昇による細胞内への取り込みの亢進により動脈硬化を促進することが明らかになった。

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  • 脂質代謝バランスの揺らぎと歯周疾患のパスウェイ解析

    2011年 - 2014年

    科学研究費  基盤研究(B) 

    山崎 和久

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    資金種別:競争的資金

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  • 口腔‐消化管の粘膜免疫システムを介した口腔感染と動脈硬化性疾患の関連機序

    2011年 - 2013年

    科学研究費  基盤研究(C) 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 口腔ー消化管の粘膜免疫システムを介した口腔感染と動脈硬化性疾患の関連機序

    研究課題/領域番号:23593056  2011年 - 2013年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    多部田 康一, 山崎 和

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    配分額:5200000円 ( 直接経費:4000000円 、 間接経費:1200000円 )

    本研究は歯周病の原因菌であるPorphyromonas gingivalisを感染させた動脈硬化症マウスモデルを用い、歯周病を想定する口腔感染に起因する消化管における宿主応答が全身の炎症応答と動脈硬化病変の進展に関与するメカニズムを明らかにすることを目的とした。口腔から摂取したPorphyromonas gingivalisは腸管において炎症応答を誘導した。新たな知見として核酸抗原(DNA 抗原、RNA抗原)を認識することのできないUnc93b欠損マウスにおいてはIgAの産生低下が認められた。この結果から消化管を介した免疫応答とIgAの産生において核酸抗原が重要な役割をもつ知見が得られた。

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  • 選択的スプライシングにおけるGU(T)-AGルールの例外-新たな骨形成不全症モデルマウスにおける病態発症機構の解明-

    2010年

    新潟大学  新潟大学 プロジェクト 推進経費 ・奨励研究B 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • レギュラトリー細胞が歯周組織破壊に及ぼす影響-敵か味方か-

    研究課題/領域番号:21390555  2009年 - 2011年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    中島 貴子, 山崎 和久, 多部田 康一, 伊藤 晴江, 下野 正基

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    配分額:17810000円 ( 直接経費:13700000円 、 間接経費:4110000円 )

    歯周病原細菌Porphyromonas gingivalisを慢性口腔感染させた歯周炎モデルマウスを用い、抑制性細胞NKT細胞の欠失あるいは活性化が歯周組織破壊に及ぼす影響とメカニズムを解析した。NKT細胞欠損マウスでは歯槽骨吸収は抑制され、NKT活性化マウスでは亢進した。NKT細胞活性化マウスではNKT細胞によるサイトカイン産生はINF-γよりもIL-4産生優位であった。さらに血清中のP. gingivalis特異抗体レベルならびにRANKLレベルの上昇を認めた。これらより、NKT細胞はTh2応答を誘導することにより歯槽骨吸収を促進させることが示唆された。

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  • レギュラトリー細胞が歯周組織破壊に及ぼす影響-敵か味方か-

    2009年 - 2011年

    科学研究費  基盤研究(B) 

    中島 貴子

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    資金種別:競争的資金

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  • 新潟大学 プロジェクト 推進経費 ・奨励研究

    2009年

    新潟大学 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 歯周炎と動脈硬化性疾患の生物学的関連を解明するーインターフェースとなるエイジング

    研究課題/領域番号:20592426  2008年 - 2010年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    多部田 康一, 山崎 和久

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    歯周炎マウスモデルを用いた解析においては、P.gingivalisの口腔内感染が全身的な炎症応答を誘導し、動脈組織における遺伝子発現の変化に加え、血清脂質の動脈硬化症リスクを高める方向への変動も誘導することが示された。動脈硬化性疾患と口腔感染の関連メカニズムとして、口腔感染が脂質代謝変動に寄与する新しい知見が得られた。またエイジングとの関連について検討を継続している。

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  • 歯周炎と動脈硬化性疾患の生物学的関連を解明する-インター フェースとなるエイジング-

    2008年 - 2010年

    科学研究費  科学研究費基盤研究(C) 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 小胞体ストレスと歯周疾患の関連―病因論の新たなパラダイム構築―

    研究課題/領域番号:20659325  2008年 - 2009年

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    山崎 和久, 中島 貴子, 多部田 康一

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    配分額:3200000円 ( 直接経費:3200000円 )

    小胞体ストレスは加齢や感染など、種々の状況においてミスフォールドしたタンパクの蓄積により活性化される細胞性の応答である。歯周炎局所では歯周病原細菌の感染により誘導される炎症反応、および同時に働く組織修復機構の過程では多種多様な分子の産生が亢進していること、そしてその結果過剰な小胞体ストレス応答が生じ、転写因子NF-κBにより制御される炎症関連分子の産生が増強されることが考えられる。これらのことから歯周炎の病態決定因子として小胞体ストレス応答の関与が疑われる。そこで、歯周炎患者25名より歯周外科手術時あるいは抜歯時に歯周炎罹患組織を、その他の患者21名より歯周炎以外の理由による抜歯時に臨床的歯肉炎あるいは臨床的健康歯肉を採取した。得られた歯肉より全RNAを抽出し、real-time PCR法により小胞体ストレス関連分子であるATF4,XBP1,CHOP,SEPS1の遺伝子発現を定量的に解析した。
    HSP60,HSP70発現については歯肉バイオプシーを用いて免疫組織化学染色により解析した。また、感染と炎症の小胞体ストレスに及ぼす影響を明らかにする目的でマクロファージを歯周病原細菌Porphyromonas gingivalisおよびEscherichia coli LPSとIFN-γで刺激した時のATF4,XBP1,CHOP,SEPS1発現を同様に解析した。その結果、歯周炎組織ではすべての小胞体ストレス関連分子の遺伝子およびHSP60タンパク発現が健康/歯肉炎組織と比較して有意に上昇していた。二重染色の結果から、HSP60発現は主としてB細胞に認められた。マクロファージのin vitro刺激においてATF4,SEPS1,CHOPは刺激時間依存的に遺伝子発現が上昇する傾向が認められた。この反応はE.coli LPSにおいてもっとも顕著であり、P.gingivalis LPSではほとんど認められず、IFN-γではE.coli LPSとほぼ同程度に遺伝子発現を上昇させる作用が認められた。これらの結果より、歯周炎組織では小胞体ストレス応答が生じていること、その応答は細菌の直接作用ではなく、むしろ局所の炎症反応で産生された炎症性サイトカインがその引き金となっていることが推測された。さらにUPRを介したNF-κBの活性化経路が存在することより、歯周炎の病態形成においてB細胞が重要な役割を演じていると考えられた。

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  • 小胞体ストレスと歯周疾患の関連―病因論の新たなパラダイム構築―

    2008年 - 2009年

    科学研究費  挑戦的萌芽研究 

    山崎 和久

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    資金種別:競争的資金

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  • 歯周炎とエイジング-歯周組織の加齢と免疫系の加齢の検証

    2008年

    新潟大学  プロジェクト 推進経費 ・奨励研究 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • メタボリックシンドロームとしての歯周炎の病態解明-感染免疫特性からのアプローチ-

    研究課題/領域番号:19390536  2007年 - 2009年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    山崎 和久, 中島 貴子, 多部田 康一, 伊藤 晴江

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    配分額:18720000円 ( 直接経費:14400000円 、 間接経費:4320000円 )

    歯周炎が全身に及ぼす影響を解明するため、歯周病原細菌による感染特性、歯周炎患者における全身的な炎症状態及び歯周治療の及ぼす効果、ネステッド・ケース・コントロール研究において歯周病原細菌感染と動脈硬化性疾患の関連について検討した。また、マウス歯周炎モデルを作成し、歯周病原細菌、Porphyromonas gingivalis感染の各種臓器・組織における動脈硬化関連遺伝子発現に及ぼす影響についても解析した。その結果、P.gingivalisには宿主の免疫監視機構を攪乱する活性があることが示された。歯周炎患者では血清CRP値、IL-6のレベルが健常人のそれと比較して有意に高く、治療により低下することが明らかになった。ネステッド・ケース・コントロール研究では多重ロジスティック回帰分析でその他のリスク因子を補正してもP.gingivalisに対する抗体価と動脈硬化性疾患の間に有意な相関があることが示された。これらの結果から、歯周疾患が動脈硬化症と関連することが強く示唆された。関連の背景にある生物学的メカニズムを明らかにするための動物実験では、ヒト歯周炎患者でみられたCRP, IL-6の上昇はもとより、歯周病原細菌の感染により血管・肝臓において炎症、脂質代謝、メタボリックシンドロームに関連する遺伝子が、いずれも動脈硬化症の発症・進展を促進するような変動を示すことが明らかになった。しかしながら、感染期間が短い場合には動脈硬化病変ができなかったことから、発症の促進、すでにできている病変の進行に関わることが示唆された。

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  • メタボリックシンドロームとしての歯周炎の病態解明-感染免疫特性からのアプローチ-

    2007年 - 2009年

    科学研究費  基盤研究(B) 

    山崎 和久

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    資金種別:競争的資金

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  • 歯周炎における新しい病因、病態論-ウイルス感染の影響-

    研究課題/領域番号:18791588  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    多部田 康一

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    配分額:3500000円 ( 直接経費:3500000円 )

    歯周炎は細菌感染によって引き起こされる慢性感染症である.一方で歯周炎組織より単純ヘルペスウィルス,サイトメガロウィルス,EBウィルスなどのウィルス核酸が検出されており,歯周炎の病態形成におけるウィルスの関与も示唆されている.細菌やウィルス由来の種を超えて保存された抗原はToll-like receptors(TLRs)で認識されるが,歯周炎組織におけるTLR familyの遺伝子発現に関する報告は少なく,特に核酸認識に関わる受容体については全く報告がない.よって本研究の目的は,歯肉炎群と歯周炎群でTLRsおよびウィルス感染により産生が誘導され,強力な抗ウィルス作用をもつinterferon-α(IFN-α)の発現を比較することにより,歯周炎の病態形成におけるウィルス関与を明らかにすることとした。
    新潟大学医歯学総合病院歯周病診療室を受診した歯周炎患者群(以下歯周炎群)59名と歯周炎に罹患していないコントロール被験者群(以下歯肉炎群)27名を被験者とした歯肉組織中のTLR familyの遺伝子発現定量解析を行った.同時にヘルペスウィルスに対する血清抗体価をELISA法にて測定した.さらに歯周炎群7名,歯肉炎群2名から歯肉組織を採取し連続凍結切片を作成,ウィルス感染おけるIFN-a産生の主体となる形質細胞様樹状細胞のマーカー分子BDCA-2に対する免疫組織学的解析を行った.
    【結果】1.TLR2,4,7,9の遺伝子発現は歯肉炎群と比較して歯周炎群において有意に高かった.(P<0.01)2.IFN-αの遺伝子発現は歯肉炎群と比較して歯周炎群において有意に高かった.(P<0.05)3.ヒトサイトメガロウィルスに対する抗体陽性率は,歯周炎群で高い傾向が見られた.4.歯周炎患者切片7例中4例においてBDCA-2陽性細胞がポケット上皮下の結合組織中に認められた。

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  • 歯周炎における新しい病因、病態論-ウイルス感染の影響-

    2006年 - 2007年

    科学研究費  若手研究(B) 

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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