The Role of STAT3 in acute inflammatory hepatitis

Concanavalin A (Con A)- induced hepatitis is a well established animal model for studying human fulminant and autoimmune hepatitis. However, the underlying mechanism is not fully understood. To clarify the role of STAT3 in Con A-induced hepatitis in hepatocyte, liver-specific STAT3 conditional knockout mice were used in our research. We previously showed that reduced serum ALT/AST and mild liver damage were observed in STAT3KO mice in response to Con A treatment. We now show that, STAT3KO hepatocytes are more resistant to the killing of Con A-activated IHLs in vitro. STAT3KO hepatocytes are also more resistant to TNF-α and Fas-agonist induced apoptosis of hepatocytes in vitro. These results suggest that STAT3 positively regulates Con A and death receptor-induced apoptotic pathway in hepatocytes in vivo and in vitro.he mechanisms of resistance of STAT3KO mice to Con A-mediated hepatitis are further investigated. While comparable levels of death receptors such as TNFR and Fas are expressed in hepatocytes of WT and STAT3KO mice before and after Con A treatment, the expression of Bcl-2 and Bcl-XL, two anti-apoptotic genes, that have been reported as STAT3 downstream gene, is also similar between WT and STAT3KO hepatocytes after treatment. Furthermore, significantly increased levels of interleukin-15 and peroxiredoxin2 are observed in STAT3KO hepatocytes when compared to WT control. Further investigation is needed to characterize the contribution of these two moleculesto resistant phenotype of STAT3KO mice during Con A-mediated hepatitis. A similar phenotype is seen when mice are injected D-galactosamine plus LPS which is also a well-known animal model for acute hepatitis. aken together, our findings suggested that STAT3 is a pro-apoptotic molecule in hepatocytes during acute inflammatory hepatitis.