Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure

Con A administration results in dose-dependent immune-mediated liver injury. Cytokines are important to determine the outcome of liver failure in this model, and especially TNF-alpha and IFN-gamma directly contribute to hepatocyte damage. The intracellular pathways of these two cytokines, which eventually result in tissue destruction, are not well defined. Here we used anti-IFN-gamma Abs and adenoviral vectors that express molecules inhibiting distinct TNF-alpha -dependent pathways in hepatocytes to better understand the relevance of specific intracellular signaling cascades for Con A-induced liver failure. We show that activation of TNF-alpha- and IFN-gamma -dependent intracellular pathways occurs prior to the influx of immune-activated cells into the liver and that anti-TNF-ce and anti-IFN-gamma neutralizing Abs cannot block infiltration of these cells. Blocking experiments with Abs and adenoviral vectors showed that NF-kappaB activation and the Fas-associated death domain protein/caspase 8 cascade in hepatocytes during Con A-induced liver failure have no impact on tissue injury. Additionally, STAT1. activation alone after Con A injection in liver cells does not result in liver damage. In contrast, IFN-gamma -dependent expression of IFN regulatory factor-1 and TNF-alpha -dependent activation of c-Jun N-terminal kinase in liver cells correlates with liver cell damage after Con A injection. Therefore, our experiments indicate that IFN regulatory factor-1 and the c-Jun N-terminal kinase pathway are involved in determining hepatocyte damage during Con A-induced liver failure and thus may provide new targets for therapeutic intervention. The Journal of Immunology, 2001.