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.

IFN Regulatory Factor-2 Regulates Macrophage Apoptosis through a STAT1/3- and Caspase-1-Dependent Mechanism

“…The relationship between STAT3 activation and apoptosis has been explored previously (53,(63)(64)(65)(66). For example, STAT3 has been shown to repress apoptosis by inhibiting caspase-3 and up-regulating Bcl-x L (14). Our results support and extend these findings: IRF-2 Ϫ/Ϫ macrophages exhibit inhibition of caspase-3 activity and up-regulation of Bcl-x L mRNA in response to gliotoxin or LPS plus IFN-␥.…”

“…Total RNA was isolated from liver samples, and 20 g of RNA was converted to cDNA with StrataScript reverse transcriptase (FairPlay Microarray Labeling Kit; Stratagene), using oligo(dT) [12][13][14][15][16][17][18] as a primer. cDNA was purified and labeled with Cy3 and Cy5 (Amersham Biosciences).…”

“…Among the STATs, STAT3 has been shown to be involved in apoptosis (11)(12)(13)(14)(15). Three distinct isoforms of STAT3 have been identified, as follows: STAT3␣ (p92), the full-length isoform expressed in most cells; STAT3␤ (p83), an alternatively spliced RNA form of STAT3␣ (16); and STAT3␥ (p72), a C-terminal truncated form of STAT3␣ derived posttranslationally through limited proteolysis (17).…”

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

“…We analyzed levels of GSH, GSSG, and redox-related protein 1 (Ref-1), which suppresses reactive oxygen species generation in mouse liver. 6 The basal ratio of GSH/total glutathione was lower in the Reg2Ϫ/Ϫ mice than in the Reg2ϩ/ϩ1 mice and resulted from the level of GSSG being higher (1.5 Ϯ 0.7 mol/g) in the Reg2Ϫ/Ϫ mice than in the Reg2ϩ/ϩ1 mice (0.78 Ϯ 0.2 mol/g, P Ͻ .01). After J0-2 treatment, GSH and GSSG levels in the Reg2Ϫ/Ϫ mice significantly decreased (P Ͻ .05), whereas those in the control Reg2ϩ/ϩ1 mice were not modified up to 4 hours after treatment.…”

“…4 Indeed, hepatocyte growth factor and cytokines (interleukin-6 [1L-6]) promoted hepatic survival by stimulating liver regeneration and provided hepatoprotection in a variety of liver injury models, including Fas. [5][6][7][8] Insulin-like growth factor binding protein-1, 9,10 amphiregulin, 11,12 and heparin-binding epidermal growth factor 13 also displayed potent hepatoprotective or mitogenic effects. Thus, the identification of critical factors for in vivo antiapoptotic and mitogenic signaling pathways is of clinical interest.…”