Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver

Background & Aims: Apoptosis of hepatocytes is a central feature of ischemic injury in the liver. The aim of this study was to identify extracellular inducers of apoptosis in the murine ischemic liver. Methods: Involvement of tumor necrosis factor (TNF)-alpha and Fas signaling was evaluated using various knockout mice (TNF-receptor 1 [TNF-R1]-/-, Fas[lpr]-/-, and Fas ligand[gld]-/-) and wild-type mice pretreated with pentoxifylline, an inhibitor of TNF-alpha synthesis. Results: Expression of TNF-alpha was increased after ischemia and reperfusion in wild-type mice and TNF-R1-deficient mice when compared with sham-operated animals. Pentoxifylline prevented up-regulation of TNF-alpha expression. Inhibition of TNF-alpha resulted in significant decrease of serum aspartate aminotransferase levels and prolonged animal survival. Markers of apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nickend labeling staining, cytochrome C release, and caspase 3 activity) were consistently decreased, and animal survival was prolonged after blocking TNF-alpha. In contrast, Inhibition of Fas signaling did not alter parameters of tissue injury or apoptosis, and animal survival remained unchanged. Conclusions: We identify TNF-alpha as a crucial inducer of apoptotic cell death in the ischemic liver. A role for Fas could not be identified. These findings may lead to novel strategies to prevent ischemic injury of the liver.