Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms

被引:224
作者
Haga, S
Terui, K
Zhang, HQ
Enosawa, S
Ogawa, W
Inoue, H
Okuyama, T
Takeda, K
Akira, S
Ogino, T
Irani, K
Ozaki, M
机构
[1] Natl Res Inst Child Hlth & Dev, Dept Innovat Surg, Setagaya Ku, Tokyo 1548567, Japan
[2] Kobe Univ, Div Diabet & Digest & Kidney Dis, Dept Clin Mol Med, Grad Sch Med, Kobe, Hyogo 657, Japan
[3] Natl Ctr Child Hlth & Dev, Dept Clin Genet & Mol Med, Tokyo, Japan
[4] Osaka Univ, Microbial Dis Res Inst, Dept Host Def, Osaka, Japan
[5] Okayama Univ, Dept Food & Hlth Sci, Grad Sch Med & Dent, Okayama, Japan
[6] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
关键词
D O I
10.1172/JCI200317970
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration. In order to investigate the hepatoprotective effects of Stat3, we examined whether Stat3 protects against Fas-mediated liver injury in the mouse. A constitutively activated form of Stat3 (Stat3-C) was adenovirally overexpressed in mouse liver by intravenous injection, and then a nonlethal dose of Fas agonist (Jo2) was injected intraperitoneally into the mouse (0.3 mug/g body wt). Stat3-C dramatically suppressed both apoptosis and necrosis induced by Jo2. In contrast, liver-specific Stat3-knockout mice failed to survive following Jo2 injection. Stat3-C upregulated expression of FLICE inhibitor protein (FLIP), Bcl-xL, and Bcl-2, and accordingly downregulated activities of FLICE and caspase-3 that were redox-independent. Interestingly, Stat3-C also upregulated the redox-associated protein redox factor-1 (Ref-1) and reduced apoptosis in liver following Jo2 injection by suppressing oxidative stress and redox-sensitive caspase-3 activity. These findings indicate that Stat3 activation protects against Fas-mediated liver injury by inhibiting caspase activities in redox-dependent and -independent mechanisms.
引用
收藏
页码:989 / 998
页数:10
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