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 1

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Stat3-C protein is successfully overexpressed in mouse liver and activat...
Stat3-C protein is successfully overexpressed in mouse liver and activates Stat3 DNA binding. (a) Anti-Stat3 and anti-FLAG immunoblots were performed to determine total and exogenous Stat3 protein in liver tissue, respectively, 3 days after adenovirus infection. (b) Immunohistochemical study using anti-Stat3 showed that Stat3-C protein is expressed in nuclei and cytoplasm of the liver in Stat3-C mice. Original magnification, ×200. (c) Electrophoretic mobility shift assay (EMSA) analysis showed elevated Stat3 DNA binding in the liver of Stat3-C mice. Five micrograms of nuclear extract was incubated with SIE-m67 probe. In order to confirm specific Stat3 DNA binding, competition (comp.) and supershift assays were performed using cold SIE-m67 probe and anti-Stat3. (d) Western blot analysis of Stat3 protein in various tissues of control and LS3-KO mice. These data are representative of at least three independent experiments. FP, free probe; ss, supershift; IB, immunoblot.