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Aggregatibacter actinomycetemcomitansによるインフラマソームの活性化

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Title: Aggregatibacter actinomycetemcomitansによるインフラマソームの活性化
Other Titles: Activation of inflammasome by Aggregatibacter actinomycetemcomitans
Authors: 阿部, 亜美 Browse this author
佐伯, 渉 Browse this author
長谷部, 晃 Browse this author →KAKEN DB
原, 博志 Browse this author
八若, 保孝 Browse this author →KAKEN DB
柴田, 健一郎 Browse this author
Keywords: Aggregatibacter actinomycetemcomitans
NLRP3 inflammasome
Issue Date: Mar-2015
Publisher: 北海道歯学会
Journal Title: 北海道歯学雑誌
Volume: 35
Issue: 2
Start Page: 123
End Page: 132
Abstract: Inflammasome is an intracellular sensor that regulates the production of IL-1β, which is one of the inflammatory cytokines with diverse biological activities. Recently, inflammasome is intensively investigated as a clue to clarify pathogenesis of many inflammatory diseases that are known to be associated with IL-1β. In periodontitis, IL-1β is known to play an important role in the pathogenesis. However, few reports on the association between periodontitis and inflammasome have been obtained, although some periodontopathogenic bacteria induced production of IL-1β exist. In this study we investigated whether Aggregatibacter actinomycetemcomitans, a major pathogen of aggressive periodontitis, as well as systemic diseases such as infectious endocarditis, induce the activation of inflammasome in a murine dendritic cell line like XS106 cells. Futher investigation was carried out,to clarify its pathogenic roles in periodontitis. Stimulation of XS106 cells with live and heat killed cells of A. actinomycetemcomitans induced production of IL-1β, whereas the cultute supernatant did not. The IL-1β production-inducing activity of live and heat killed cells was significantly inhibited by Z-YVAD-FMK and Z-VAD-FMK, which are inhibitors for caspase 1 and all caspases, respectively. In addition, the activity was significantly attenuated by the decrease of mRNAs of caspase-1 and NLRP3. Furthermore, both heat-killed and live cells induced necrosis-like cell death in XS106 cells, which is considered to be pyroptosis because of its accompanying the production of IL-1β. Thus, these results suggest that A. actinomycetemcomitans activates NLRP3 inflammasome in murine dendritic cells producing IL-1β, which is released extracellularly by pyroptosis.
インフラマソームは多様な生理活性をもつ炎症性サイトカインのひとつであるIL-1βの産生を制御する細胞内センサーである.近年,IL-1βが関与する炎症性疾患の多くがこの細胞内センサーの活性化と関連している可能性が示唆され,病態解明の手がかりとしてインフラマソームが注目されている.歯周炎はその病態形成にIL-1βが重要な役割を果たすが,歯周炎とインフラマソームとの関連を示した報告はほとんどない.そこで,本研究では,侵襲性歯周炎の主な病原菌であり,感染性心内膜炎や敗血症などの全身疾患との関連も多く報告されているAggregatibacter actinomycetemcomitansの歯周疾患における病因論の一部を明らかにすることを目的とし,本菌によるインフラマソームの活性化について検証した.A. actinomycetemcomitansの生菌および死菌でA/Jマウス由来樹状細胞(XS106細胞)を刺激したところ,生菌,死菌ともにIL-1βの産生を誘導したが,A. actinomycetemcomitans培養上清では産生誘導はみられなかった.生菌および死菌でのIL-1β産生誘導活性はZ-VAD-FMKとZ-YVAD-FMKで有意に阻害された.さらに,これらのIL-1β産生誘導活性はcaspase-1ならびにNLRP3のノックダウンにより有意に減弱した.また,A. actinomycetemcomitans菌体はXS106細胞にネクローシス様細胞死を誘導し,その細胞死はIL-1βの産生を伴うことからピロトーシスであると考えられる.  以上の結果から,A. actinomycetemcomitans菌体はXS106細胞においてNLRP3インフラマソームを活性化し,IL-1β産生ならびにピロトーシス誘導活性を有していることがわかった.
Type: article
Appears in Collections:北海道歯学雑誌 = Hokkaido Journal of Dental Science > 第35巻 第2号

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