TNFR1 controls apoptosis and chronic liver disease in hepatocyte-specific IKKgamma (Nemo) mice

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-kappaB essential modulator in hepatocytes (NemoDeltahepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in NemoDeltahepa mice. Therefore, we generated NemoDeltahepa/TRAIL-/- and NemoDeltahepa/TNFR1-/- animals and analyzed the progression of liver injury. NemoDeltahepa/TRAIL-/- displayed a similar phenotype to NemoDeltahepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in NemoDeltahepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in NemoDeltahepa and NemoDeltahepa/TRAIL-/- mice while NemoÎDeltahepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in NemoDeltahepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice. Expression profiling of livers from wild type, NEMO, NEMO-TRIAL, and NEMO-TNFR null mice