Hepatocellular apoptosis is mediated by TNFα-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure

There is increasing evidence that the active contribution of hepatocytes to liver disease is strongly dependent on local cytokine environment. It has been shown in vitro that TNF alpha can enhance hepatocyte FasLigand (FasL)-mediated cytotoxicity. Here, we demonstrate that TNF alpha-induced apoptosis was associated with Fas and FasL upregulation and that a FasL-neutralizing antibody prevented TNF alpha-induced apoptosis. We further examined in vivo the relevance of the Fas/FasL pathway to hepatocellular apoptosis in a TNF alpha-driven model of acute liver failure. Livers of galactosamine/lipopolysaccharide (Gal/LPS)-exposed Fas wild-type mice highly expressed both Fas and FasL and revealed marked hepatocellular apoptosis that was almost completely blocked by soluble TNF alpha-receptor; this was also almost absent in Gal/LPS-exposed Fas lymphoproliferation mutant mice. Our data provide evidence for a direct link between TNF alpha and Fas/FasL in mediating hepatocyte apoptosis. Fratricidal death by Fas-FasL interactions of neighbouring hepatocytes may actively contribute to acute liver failure.