STAT3在Con A 引起肝炎反應中促進肝細胞進行細胞凋亡的角色研究

Abstract

Concanavalin A (Con A)-induced hepatitis is considered as a model for human fulminant hepatitis. Although this model has been established for decades, the underlying mechanisms are still not fully understood. In order to clarify the role of STAT3 in liver during Con A-induced hepatitis, liver-specific STAT3 conditional knockout mice were used. In our previous studies, reduced serum ALT/AST levels, liver injury and apoptosis were observed in STAT3KO mice after Con A treatment. Higher survival rate was also shown in STAT3KO mice after challenging mice with high-dose Con A. Moreover, STAT3KO hepatocytes were more resistant to in vitro killing of Con A-activated IHLs. These data suggested that STAT3 had a pro-apoptotic role in hepatocytes in Con A-induced hepatitis. The mechanisms of resistance of STAT3KO mice to Con A-induced hepatitis were further investigated. First of all, lower expressions of p55α and p50α, two isoforms of p85α regulatory subunits, were observed in liver and primary hepatocytes of STAT3KO mice both in in vivo and in vitro experiments. Secondly, enhanced Akt activity was observed in STAT3KO mice after administration of Con A. These results suggested that the reduced conversion of PI3 kinase regulatory subunits from p85α to p55α and p50α might contribute to the reduced hepatitis in STAT3KO mice. To investigate if the differential response to cytokine-induced apoptosis also resulted in the resistance of STAT3KO mice in Con A-induced hepatitis, primary hepatocytes were stimulated with TNF-α/IL-6 in vitro. Decreased TNF-α-induced apoptosis was found in STAT3KO hepatocytes and the IL-6-mediated enhancement of TNF-α-induced apoptosis in hepatocytes was not blocked in the absence of STAT3. Finally, impaired SOCS3 and enhanced SOCS1 expression were detected in STAT3KO heaptocytes before and after stimulation, implying the differential SOCS production might affect cytokine signaling pathways and contributed to reduced Con A-induced hepatitis in STAT3KO mice. Taken together, these results suggested that STAT3 is a positive regulator for Con A-induced hepatitis probably by affecting the conversion of p85α to p55α and p50α of PI3 kinase, regulating the response through IL-6-STAT3 signaling to enhance TNF-α-induced apoptosis or altering cytokine responses via atypical SOCS production.