Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms
Sanae Haga, … , Kaikobad Irani, Michitaka Ozaki
Sanae Haga, … , Kaikobad Irani, Michitaka Ozaki
Published October 1, 2003
Citation Information: J Clin Invest. 2003;112(7):989-998. https://doi.org/10.1172/JCI17970.
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Article Genetics

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

Abstract

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 μg/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.

Authors

Sanae Haga, Keita Terui, Hui Qi Zhang, Shin Enosawa, Wataru Ogawa, Hiroshi Inoue, Torayuki Okuyama, Kiyoshi Takeda, Shizuo Akira, Tetsuya Ogino, Kaikobad Irani, Michitaka Ozaki

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Figure 6

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Hepatic ROS production and apoptosis induced by Fas agonist are suppress...
Hepatic ROS production and apoptosis induced by Fas agonist are suppressed by Stat3-C via Ref-1. LacZ, Stat3-C:LacZ, and Stat3-C:AdFer (Stat3-C:Fer) mice were infected with AdLacZ only, AxCAS3-C:AdLacZ (1:1), and AxCAS3-C:AdFer (1:1), respectively. Total amounts of adenovirus vectors were adjusted to 3 × 108 PFU/mouse in all experiments. (a) Immunoblots of Ref-1 and Stat3 proteins showing that AxCAS3-C increased Stat3 and Ref-1 proteins, but AdFer reduced them. Ref-1 protein was, however, expressed even in the liver of LS3-KO mice. (b) Superoxide generation assay and hydrogen peroxide assay in liver tissue*P < 0.05 vs. LacZ, **P < 0.05 vs. LacZ/Fas agonist, ***P < 0.05 vs. Stat3-C:LacZ/Fas agonist. Casp inh; i.e. Z-VAD-fmk. (c) Apoptotic cell death was quantitatively analyzed by ELISA. *P < 0.01 vs. LacZ, **P < 0.05 vs. LacZ/Fas agonist, ***P < 0.05 vs. Stat3-C:LacZ/Fas agonist. (d) Enzyme activity assays of caspase-3 and caspase-8. *P < 0.05 vs. LacZ/Fas agonist. All data are expressed as mean ± SEM (n = 5). RLU, relative light unit.