Opposing roles of STAT1 and STAT3 in T cell–mediated hepatitis: regulation by SOCS

Abstract

T cell–mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell–mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4+ and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-γ–deficient mice indicate that IFN-γ not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6–deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A–mediated hepatitis by activation of CD4+ and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-γ signaling and induction of antiapoptotic protein Bcl-XL. STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.