Critical contribution of nuclear factor erythroid 2-related factor 2 (NRF2) to electrophile-induced Interleukin-11 Production

DOI IR HANDLE Open Access
  • NISHINA Takashi
    Department of Biochemistry, Toho University School of Medicine
  • DEGUCHI Yutaka
    Department of Biochemistry, Toho University School of Medicine
  • MIURA Ryosuke
    Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science
  • YAMAZAKI Sou
    Department of Biochemistry, Toho University School of Medicine
  • SHINKAI Yasuhiro
    Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba
  • KOJIMA Yuko
    Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine
  • OKUMURA Ko
    Atopy Research Center, Juntendo University Graduate School of Medicine
  • KUMAGAI Yoshito
    Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba
  • NAKANO Hiroyasu
    Department of Biochemistry, Toho University School of Medicine

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Other Title
  • 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

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Abstract

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 J2 (PGJ2) or tert-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H2O2-induced IL-11 production, 1,2-NQ, but not 15d-PGJ2 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 Il11 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 H2O2-induced IL11 up-regulation, NRF2 was essential for 1,2-NQ-induced IL11 up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of FOSL1. Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in Il11ra1−/− mice compared with Il11ra1+/− mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.

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