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 4

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Stat3-C induces apoptosis-related proteins and redox-related protein. Im...
Stat3-C induces apoptosis-related proteins and redox-related protein. Immunoblot, Northern blot, and multiprobe ribonuclease protection assay were performed on liver tissues from PS, LacZ, and Stat3-C mice. Sequential changes of the protein amounts after Fas agonist treatment were analyzed in LacZ and Stat3-C mice. Each blot is representative of three independent experiments. (a) Expression of Fas, Bcl-related proteins, and Survivin. (b) Expression of caspase-related proteins. (c) Enzyme activity assays of caspase-3 and caspase-8. *P < 0.05 vs. LacZ, **P < 0.01 vs. LacZ/Fas agonist. (d) Protein expression of redox-related proteins Ref-1, thioredoxin, and MnSOD. (e) Multiprobe ribonuclease protection assay for apoptosis-related genes and redox-related genes 48 hours after adenoviral gene transfer. m, mouse; h, human. (f) Northern blot analysis for Ref-1 mRNA after adenoviral gene transfer of Stat3-C. Results are from a single representative experiment that was reproduced once (d–f). (g) Transcriptional activity of Ref-1 promoter by Stat3-C. Luciferase assay for Ref-1 promoter activity stimulated by AxCAS3-C or AdLacZ. Control was pGL3 without Ref-1 promoter. *P ≤ 0.01 vs. uninfected (0 MOI, 0) and LacZ (25 MOI), **P ≤ 0.01 vs. uninfected (0 MOI) and LacZ (125 MOI). All data are expressed as mean ± SEM (n = 5).