title: Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production.
abstract: 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-PGJ2or 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.
authors.affiliation: From the Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishina
authors.affiliation: From the Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Deguchi
authors.affiliation: From the Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540.|the Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Miura
authors.affiliation: From the Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540.
authors.forename: Soh
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: the Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shinkai
authors.affiliation: the Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, and.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: the Atopy Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: the Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: From the Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, hiroyasu.nakano@med.toho-u.ac.jp.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017370:Interleukin-11 / Q000096:biosynthesis*; D053703:Interleukin-11 Receptor alpha Subunit / Q000502:physiology; D007410:Intestinal Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000633:toxicity*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D000970:Antineoplastic Agents; C508429:Il11ra1 protein, mouse; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D051267:NF-E2-Related Factor 2; D009285:Naphthoquinones; D016877:Oxidants; D017382:Reactive Oxygen Species; C037112:9-deoxy-delta-9-prostaglandin D2; C040756:1,2-naphthoquinone; D006861:Hydrogen Peroxide; D015230:Prostaglandin D2
keywords: AP1 transcription factor (AP-1); Fra-1; electrophile; extracellular signal-regulated kinase (ERK); interleukin; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); oxidative stress