親電子リガンドによるIL-11産生機構とその生体における役割の解明 Critical contribution of nuclear factor erythroid 2-related factor 2 (NRF2) to electrophile-induced Interleukin-11 Production

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著者

    • 三浦 亮介 MIURA Ryosuke
    • 東京理科大学 基礎工学部 生物工学科 免疫学研究室 Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science
    • 山﨑 創 YAMAZAKI Sou
    • 東邦大学 医学部 生化学講座 Department of Biochemistry, Toho University School of Medicine
    • 新開 泰弘 SHINKAI Yasuhiro
    • 筑波大学 医学医療系 環境生物学研究室 Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba
    • 小島 裕子 KOJIMA Yuko
    • 順天堂大学 医学部 研究基盤センター 形態解析イメージング研究室 Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine
    • 奥村 康 OKUMURA Ko
    • 順天堂大学 医学部 アトピー疾患センター Atopy Research Center, Juntendo University Graduate School of Medicine
    • 熊谷 嘉人 KUMAGAI Yoshito
    • 筑波大学 医学医療系 環境生物学研究室 Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba

抄録

NRF2 is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J<sub>2</sub> (PGJ<sub>2</sub>) or <i>tert</i>-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H<sub>2</sub>O<sub>2</sub>-induced IL-11 production, 1,2-NQ, but not 15d-PGJ<sub>2</sub> or tBHQ, elicited prolonged ERK activation. Conversely, inhibition of the ERK pathway completely blocked 1,2-NQ-induced IL-11 production. Promoter analysis of the <i>Il11 </i>gene revealed that two AP-1 sites were essential for 1,2-NQ-induced promoter activities. Among various members of the AP-1 family, Fra-1 was up-regulated by 1,2-NQ, and its up-regulation was blocked by a MEK inhibitor. Although NRF2 was not required for H<sub>2</sub>O<sub>2</sub>-induced <i>IL11</i> up-regulation, NRF2 was essential for 1,2-NQ-induced <i>IL11</i> up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of <i>FOSL1</i>. Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in <i>Il11ra1</i><sup>−/−</sup> mice compared with <i>Il11ra1</i><sup>+/−</sup> mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.

NRF2 is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J<sub>2</sub> (PGJ<sub>2</sub>) or <i>tert</i>-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H<sub>2</sub>O<sub>2</sub>-induced IL-11 production, 1,2-NQ, but not 15d-PGJ<sub>2</sub> or tBHQ, elicited prolonged ERK activation. Conversely, inhibition of the ERK pathway completely blocked 1,2-NQ-induced IL-11 production. Promoter analysis of the <i>Il11 </i>gene revealed that two AP-1 sites were essential for 1,2-NQ-induced promoter activities. Among various members of the AP-1 family, Fra-1 was up-regulated by 1,2-NQ, and its up-regulation was blocked by a MEK inhibitor. Although NRF2 was not required for H<sub>2</sub>O<sub>2</sub>-induced <i>IL11</i> up-regulation, NRF2 was essential for 1,2-NQ-induced <i>IL11</i> up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of <i>FOSL1</i>. Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in <i>Il11ra1</i><sup>−/−</sup> mice compared with <i>Il11ra1</i><sup>+/−</sup> mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.

収録刊行物

  • 日本毒性学会学術年会

    日本毒性学会学術年会 44.1(0), O-35, 2017

    日本毒性学会

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