Hepatocellular apoptosis is mediated by TNFα-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure
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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 TNFα can enhance hepatocyte FasLigand (FasL)-mediated cytotoxicity. Here, we demonstrate that TNFα-induced apoptosis was associated with Fas and FasL upregulation and that a FasL-neutralizing antibody prevented TNFα-induced apoptosis. We further examined in vivo the relevance of the Fas/FasL pathway to hepatocellular apoptosis in a TNFα-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 TNFα-receptor; this was also almost absent in Gal/LPS-exposed Fas lymphoproliferation mutant mice. Our data provide evidence for a direct link between TNFα and Fas/FasL in mediating hepatocyte apoptosis. Fratricidal death by Fas–FasL interactions of neighbouring hepatocytes may actively contribute to acute liver failure.
KeywordsCaspase-3 Flow cytometry HepG2 cells Liver enzymes Microcirculation
The authors cordially thank Berit Blendow, Doris Butzlaff, Dorothea Frenz, Maren Nerowski, and Hartmut Stein (Institute for Experimental Surgery, University of Rostock, Germany) for excellent technical assistance, and Saleh Ibrahim (Immunogenetics Group, University of Rostock) for fruitful discussions and reviewing the manuscript. This study was supported by a grant from the Deutsche Forschungsgemeinschaft, Bonn Bad-Godesberg, Germany (Vo 450/8-1).
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