親電子リガンドによるIL-11産生機構とその生体における役割の解明  [in Japanese] Critical contribution of nuclear factor erythroid 2-related factor 2 (NRF2) to electrophile-induced Interleukin-11 Production  [in Japanese]

NRF2 is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity. 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 <i>tert</i>-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 completely blocked 1,2-NQ-induced IL-11 production. Promoter analysis of the <i>Il11 </i>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 <i>IL11</i> up-regulation, NRF2 was essential for 1,2-NQ-induced <i>IL11</i> up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of <i>FOSL1</i>. Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in <i>Il11ra1</i>^−/− mice compared with <i>Il11ra1</i>^+/− mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.

NRF2 is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity. 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 <i>tert</i>-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 completely blocked 1,2-NQ-induced IL-11 production. Promoter analysis of the <i>Il11 </i>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 <i>IL11</i> up-regulation, NRF2 was essential for 1,2-NQ-induced <i>IL11</i> up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of <i>FOSL1</i>. Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in <i>Il11ra1</i>^−/− mice compared with <i>Il11ra1</i>^+/− mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.