Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production

• DOI: 10.1074/jbc.m116.744755
• Publication Date: 2016-11-22T03:10:23Z
• Authors: Takashi Nishina; Yutaka Deguchi; Ryosuke Miura; Soh Yamazaki; Yasuhiro Shinkai; Yuko Kojima; Ko Okumura; Yoshito Kumagai; Hiroyasu Nakano
• Keywords: Mice, Knockout; 0301 basic medicine; MAP Kinase Signaling System; NF-E2-Related Factor 2; Antineoplastic Agents; Hep G2 Cells; Hydrogen Peroxide; Peritonitis; Interleukin-11; Oxidants; 3. Good health; Mice, Inbred C57BL; Intestinal Diseases; Mice; Oxidative Stress; 03 medical and health sciences; HEK293 Cells; Gene Expression Regulation; Animals; Humans; Interleukin-11 Receptor alpha Subunit; Cells, Cultured; Naphthoquinones

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 up-regulating phase II detoxifying enzymes and phase III transporters. 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 by a MEK inhibitor completely blocked 1,2-NQ-induced IL-11 production at both protein and mRNA levels, further substantiating an intimate cross-talk 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 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.