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

Abstract

Edited by Joel GottesfeldNuclear 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 J 2 (PGJ 2 ) or tert-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H 2 O 2 -induced IL-11 production, 1,2-NQ, but not 15d-PGJ 2 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 upregulated by 1,2-NQ, and its up-regulation was blocked by a MEK inhibitor. Although NRF2 was not required for H 2 O 2 -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.Electrophiles are electron-deficient compounds that can accept an electron pair to form a covalent bond with its reaction partner (nucleophile), resulting in adducts of macromolecules (e.g. proteins, lipids, and DNA) (1). Such reactive species have been shown to be involved in stress, aging, and cancer through modification of various signaling molecules. It is well recognized that endogenous electrophiles, such as 8-nitro-cGMP, 15-deoxy-prostaglandin J 2 (15d-PGJ 2 ), 3 and nitrated fatty acids, are produced during oxidative stress and inflammation (2, 3) and then activate redox signal transduction pathways associated with up-regulation of antioxidant and anti-inflammation genes (1-3). In addition, there are a variety of electrophiles in the environment (4, 5). For example, particles with an aerodynamic diameter of 2.5 m or less (PM2.5) and tobacco smoke (6) contain an atmospheric electrophile, 1,2-naphtoquinone (1,2-NQ), that activates epidermal growth factor receptor (EGFR) through S-arylation of Cys-121 of protein-tyrosine phosphatase 1B (PTP1B) (7). A transcription factor, NF-E2-related factor 2 (NRF2), is activated and attenuates electrophile-ind...

Interleukin-11 is a Marker for Both Cancer- and Inflammation-Associated Fibroblasts that Contribute to Colorectal Cancer Progression

“…Since IL-11 + CAFs might promote tumor development, it is crucial to investigate the mechanisms by which inflammation or tumor cells induce IL-11 expression. We previously reported that oxidative stress induces Il11 mRNA expression in an ERK/Fra-1-dependent manner 22, 23 . Thus, we tested whether DSS treatment induced oxidative stress in the colon.…”

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