Activation of the 55 kDa TNF receptor is necessary and sufficient for TNF-induced liver failure, hepatocyte apoptosis, and nitrite release.
The systemic inflammatory response is characterized by release of circulating TNF which may cause multiorgan failure including septic liver failure. We studied TNF signaling in an appropriate in vitro system with primary murine hepatocyte cultures from normal and genetically altered animals. Either one of the three different TNF species, huTNF-alpha, huTNF-beta, or muTNF-alpha (at concentrations > 1 ng/ml) induced direct hepatocytotoxicity preceded by DNA fragmentation in cells prepared from wild-type C57BL mice. TNF-induced cytotoxicity was preceded by oligonucleosomal DNA fragmentation. Further cellular responses to TNF exposure were induction of nitric oxide synthase and secretion of serum amyloid A. None of the above events occurred in hepatocytes lacking the gene for the 55-kDa TNF receptor (TNF-R1), even after stimulation with > 1 micrograms/ml TNF. However, selective stimulation of the TNF-R1 in wild-type hepatocytes with huTNF-alpha elicited a pattern of responses essentially similar to that seen with muTNF-alpha. We obtained analogous results when we examined the hepatotoxicity of TNF in D-galactosamine-sensitized mice, i.e., DNA fragmentation and liver failure was noted in wild-type mice, whereas TNF-R1-deficient mice were completely resistant. We conclude that the TNF-R1 is not only necessary, but also sufficient for TNF signaling in murine hepatocytes.
Leist
M
M
Department of Biochemical Pharmacology, University of Konstanz, Germany.
Gantner
F
F
Jilg
S
S
Wendel
A
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D008099:Liver / Q000166:cytology; D017093:Liver Failure / Q000209:etiology / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000096:biosynthesis*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide