Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production

Abstract

Recently, DNA methylation and reduced expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in human hepatocellular carcinoma (HCC) patients have been reported. However, the roles of SOCS3 in HCC development in vivo have not been clarified. Using RT-PCR analysis and Western blotting, we confirmed that SOCS3 expression was reduced in HCC patients. However, reduced expression of SOCS3 occurred not only in HCC but also in nontumor regions, and this reduction was stronger as the fibrosis grade increased. Furthermore, SOCS3 levels were inversely correlated with signal transducers and activators of transcription-3 (STAT3) activation as well as transforming growth factor (TGF)-b1 levels in the non-HCC region. To define the molecular consequences of SOCS3 silencing/STAT3 hyperactivation and liver fibrosis, we examined liverspecific SOCS3-deficient mice. We demonstrated that SOCS3 deletion in the liver resulted in hyperactivation of STAT3 and promoted ConA-and chemical-induced liver fibrosis. The expression of TGF-b1, a mediator of fibrosis, was enhanced by SOCS3 gene deletion, but suppressed by the overexpression of a dominant-negative STAT3 or SOCS3 both in vivo and in vitro. These data suggest that TGF-b1 is a target gene of STAT3 and could be one of the mechanisms for enhanced fibrosis in SOCS3-deficient mice. Thus, our present study provides a novel role of SOCS3 and STAT3 in HCC development: in addition to the previously characterized oncogenic potentials, STAT3 enhances hepatic fibrosis through the upregulation of TGF-b1 expression, and SOCS3 prevents this process.

Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

“…Phenotypic effects of IEC-SOCS3 deletion on colon tumorigenesis were associated with enhanced activation of STAT3, NF-kB and STAT1, indicating that during chronic inflammation, SOCS3 normally limits activation of multiple signaling pathways implicated in risk of CAC. Effects of SOCS3 deletion on STAT3 activation are consistent with data in other cell types, suggesting that the major role of SOCS3 is to limit hyperactivation of STAT3 by proinflammatory cytokines, particularly IL-6 (Croker et al, 2003;Ogata et al, 2006a). Findings that SOCS3 effectively inhibits STAT3 activation by IL-6 trans-signaling, as well as by IL-6 alone is relevant to evidence for a major role of IL-6 trans-signaling in CAC (Becker et al, 2004).…”

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

“…28,29 It has been also proposed that IL-10 is able to inhibit HSC activation and to promote their apoptosis during liver fibrogenesis. 28,29 Beside its well-known interference with the pro-inflammatory cytokine signaling pathways, 30,31 SOCS3 has been found to negatively regulate fibrogenesis in the liver 32,33 and to suppress the signaling molecule STAT3, which activates TGF-b transcription. 32 Our data demonstrate that the hepatic expression of all these molecules are deeply affected in cirrhosis leading to a pro-fibrogenic environment, which is fully counteracted by CB1 receptor antagonism.…”

Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

“…It was reported that STAT3 positively regulates TGF-b1 promoter activity and enhances TGF-b1 production (14,15). Intracellular staining revealed significantly enhanced STAT3 phosphorylation in the Egr-3-transduced CD4 + cells compared with the GFPnegative cells (Fig.…”

“…Th3 cells (12) and CD4 + CD25 2 latency-associated peptide (LAP) + T cells (13) are reported to secrete TGF-b1; however, the regulation of TGF-b1 secretion is not fully understood. It was reported that STAT3 positively regulates TGF-b1 promoter activity and enhances TGF-b1 production (14,15). Han et al (16) reported that the binding of CD69 maintains the expression of membranebound TGF-b1 on CD4 + CD25 2 CD69 + T cells via ERK activa-tion.…”