ACTIVATION OF THE 55-KDA TNF RECEPTOR IS NECESSARY AND SUFFICIENT FORTNF-INDUCED LIVER-FAILURE, HEPATOCYTE APOPTOSIS, AND NITRITE RELEASE

The systemic inflammatory response is characterized by release of circ ulating TNF which may cause multiorgan failure including septic liver failure. We studied TNF signaling in an appropriate in vitro system wi th primary murine hepatocyte cultures from normal and genetically alte red animals. Either one of the three different TNF species, huTNF-alph a, huTNF-beta, or muTNF-alpha (at concentrations >1 ng/ml) induced dir ect hepatocytotoxicity preceded by DNA fragmentation in cells prepared from wild-type C57BL mice. TNF-induced cytotoxicity was preceded by o ligonucleosomal DNA fragmentation. Further cellular responses to TNF e xposure were induction of nitric oxide synthase and secretion of serum amyloid A. None of the above events occurred in hepatocytes lacking t he gene for the 55-kDa TNF receptor (TNF-R1), even after stimulation w ith >1 mu g/ml TNF. However, selective stimulation of the TNF-R1 in wi ld-type hepatocytes with huTNF-alpha elicited a pattern of responses e ssentially similar to that seen with muTNF-alpha. We obtained analogou s results when we examined the hepatotoxicity of TNF in D-galactosamin e-sensitized mice, i.e., DNA fragmentation and liver failure was noted in wild-type mice, whereas TNF-R1-deficient mice were completely resi stant. We conclude that the TNF-R1 is not only necessary, but also suf ficient for TNF signaling in murine hepatocytes.