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北海道歯学雑誌 = Hokkaido Journal of Dental Science >
第38巻 第2号 >

Aggregatibacter actinomycetemcomitansのゲノムDNAはマクロファージに対してnucleotide-binding domain-like receptor containing protein 3インフラマソームを活性化してIL-1βを誘導する

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Title: Aggregatibacter actinomycetemcomitansのゲノムDNAはマクロファージに対してnucleotide-binding domain-like receptor containing protein 3インフラマソームを活性化してIL-1βを誘導する
Other Titles: Genomic DNA of Aggregatibacter actinomycetemcomitans activates the nucleotide-binding domain-like receptor containing protein 3 inflammasome to iduce IL-1β by murine macrophages
Authors: 亀崎, 良助1 Browse this author
阿部, 亜美2 Browse this author
佐伯, 歩3 Browse this author →KAKEN DB
長谷部, 晃4 Browse this author →KAKEN DB
鈴木, 敏彦5 Browse this author
北川, 善政6 Browse this author →KAKEN DB
柴田, 健一郎7 Browse this author →KAKEN DB
Authors(alt): Kamezaki, Ryosuke1
Abe, Tsugumi2
Saeki, Ayumi3
Hasebe, Akira4
Suzuki, Toshihiko5
Kitagawa, Yoshimasa6
Shibata, Ken-ichiro7
Keywords: Aggregatibacter actinomycetemcomitans
nucleotide-binding domain-like receptor containing protein 3(NLRP3)
Issue Date: Mar-2018
Publisher: 北海道歯学会
Journal Title: 北海道歯学雑誌
Volume: 38
Issue: 2
Start Page: 177
End Page: 184
Abstract: 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一つであるIL-1βの産生を制御する細胞内センサーである.IL-1βは歯周炎を含む多くの炎症性疾患において重要な病因的役割を果たしている.そこで,本研究では,侵襲性歯周炎の主な病原菌であるAggregatibacter actinomycetemcomitans によるnucleotide-bindingdomain-like receptor containing protein 3(NLRP3)インフラマソームの活性化を介したIL-1β産生誘導について検証した.C57BL/6(B6)マウスならびにcaspase-1,ASC(apoptosis-associated speck-like protein containinga caspase recruitment domain)あるいはNLRP3をノックアウトしたマウスより採取した骨髄細胞から分化誘導したマクロファージ(BMM)をA. actinomycetemcomitans JP2の生菌および100℃で5分間熱処理した死菌で刺激した.IL-1βはELISA法ならびにウェスタンブロッティング法で測定した.生菌ならびに死菌でB6 BMM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,生菌に比べて死菌の活性が約10倍高かった.生菌および死菌の活性はcaspase-1-/-,ASC-/-ならびに NLRP3-/-のBMMでは殆ど消失した.また,死菌の活性はDNA分解酵素処理で有意に減弱し,さらに菌体の熱処理後の遠心上清には生菌に比べて約5倍量のDNAが検出された.そこで,本菌のゲノムDNAを抽出し,B6 BMMを刺激したところ,濃度依存的にIL-1βの産生が誘導されたが,caspase-1-/-,ASC-/-ならびに NLRP3-/-のBMMでは有意に減弱した.以上の結果から,A. actinomycetemcomitansはマクロファージに対してNLRP3インフラマソームを活性化してIL-1βの産生を誘導する活性物質を有しており,その活性物質の一つはDNAであることが示唆された.
Inflammasome is an intracellular sensor that regulates the production of IL-1β and IL-18 which are inflammatory cytokines with diverse biological activities. IL-1β plays important pathological roles in many inflammatory diseases including periodontitis. In this study, we investigated whether Aggregatibacter actinomycetemcomitans (Aa), a major pathogen of aggressive periodontitis, induces the activation of inflammasome in macrophages to produce IL-1β. Live or heat-killed (100 ℃, 5 min) cells of Aa were used as bacterial cells. Bone marrow-derived macrophages (BMMs) from C57BL/6 (B6), caspase-1-, ASC- and NLRP3-deficient mice were used for target cells. Live and heat-killed cells of Aa have the activity to induce IL-1β production by B6-derived BMM. The activity of heat-killed cells is almost 10-fold higher than that of live cells. The activities of both live and heat-killed cells were significantly attenuated in BMMs from caspase-1-, ASC- and NLRP3-dificient mice, suggesting that Aa activates the NLRP3 inflmmasome to induce IL-1β production. The activity of heat-killed cells was significantly inhibited by DNase treatment and it was found that genomic DNA was released into the cell-free medium by heat treatment. In addition, genomic DNA prepared from live cells of Aa induced IL-1β production by BMM in a dose dependent manner and the activity was dependent on the NLRP3 inflammasome. Thus, these results suggest that Aa activates NLRP3 inflammasome in murine BMM to produce IL-1β, and one of the active entities is its genomic DNA.
Type: article
Appears in Collections:北海道歯学雑誌 = Hokkaido Journal of Dental Science > 第38巻 第2号

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