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

J Biol Chem. 2017 Jan 6;292(1):205-216. doi: 10.1074/jbc.M116.744755. Epub 2016 Nov 21.


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.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity
  • Cells, Cultured
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Interleukin-11 / biosynthesis*
  • Interleukin-11 Receptor alpha Subunit / physiology
  • Intestinal Diseases / chemically induced
  • Intestinal Diseases / metabolism
  • Intestinal Diseases / pathology
  • Intestinal Diseases / prevention & control*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Naphthoquinones / toxicity*
  • Oxidants / pharmacology
  • Oxidative Stress / drug effects
  • Peritonitis / chemically induced
  • Peritonitis / metabolism
  • Peritonitis / pathology
  • Peritonitis / prevention & control*
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / toxicity
  • Reactive Oxygen Species / metabolism


  • 15-deoxyprostaglandin J2
  • Antineoplastic Agents
  • Il11ra1 protein, mouse
  • Interleukin-11
  • Interleukin-11 Receptor alpha Subunit
  • NF-E2-Related Factor 2
  • Naphthoquinones
  • Oxidants
  • Reactive Oxygen Species
  • 9-deoxy-delta-9-prostaglandin D2
  • 1,2-naphthoquinone
  • Hydrogen Peroxide
  • Prostaglandin D2