ニシナ タカシ   Nishina Takashi
  仁科 隆史
   所属   東邦大学  医学部 医学科
   職種   助教
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 Critical contribution of NRF2 to an electrophile-induced interleukin-11 production
掲載誌名 正式名:J Biol Chem
ISSNコード:1083-351X
巻・号・頁 292,205-216頁
著者・共著者 Nishina, T. Deguchi, Y. Miura, R. Yamazaki, S. Shinkai, Y. Kojima, Y. Okumura, K. Kumagai, Y. Nakano, H.
発行年月 2017/01
概要 Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through upregulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces upregulation 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 (PG)J2, or tert-buthyl hydroxyquinone (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 by a MEK inhibitor completely blocked 1,2-NQ-induced IL-11 production at both protein and mRNA levels, further substantiating an intimate crosstalk between ERK activation and 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 upregulated by 1,2-NQ and its upregulation was blocked by a MEK inhibitor. While NRF2 was not required for H2O2-induced IL11 upregulation, NRF2 was essential for 1,2-NQ-induced IL11 upregulation 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 to Il11ra1+/- mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ-intestinal toxicity.
DOI 10.1074/jbc.M116.744755