Tumor Necrosis Factor α Prevents Tumor Necrosis Factor Receptor—Mediated Mouse Hepatocyte Apoptosis, But Not Fas–Mediated Apoptosis: Role of Nuclear Factor–κB

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Abstract
Tumor necrosis factor α (TNF–α) binding to the TNF receptor (TNFR) initiates apoptosis and simultaneously activates the transcription factor, nuclear factor–κB (NF–κB), which suppresses apoptosis by an unknown mechanism. Pretreatment with TNF–α or interleukin–1β (IL–1β), which activated NF–κB in the liver, dramatically prevented TNF–α–induced liver–cell apoptosis in D–galactosamine (GalN)–sensitized mice, but not anti–Fas antibody–induced hepatotoxicity. This protective effect of TNF–α continued for 5 hours after TNF–α administration, a time course similar to that found in NF–κB activation after TNF–α administration. In mice treated with adenoviruses expressing a mutant form of IκB, the antiapoptotic effect of TNF–α was inhibited in part. Prior TNF–α administration was not found to block the activation of caspase–8, although caspase–3 was inhibited in mice treated with TNF–α plus GalN/TNF–α compared with mice treated with GalN/TNF–α. These results indicate that TNFR and Fas independently regulate murine apoptotic liver failure, and that a rapid defense mechanism induced by the activation of NF–κB blocks death–signaling at the initiation stage of hepatic apoptosis mediated by TNFR, probably downstream of caspase–8, but not by Fas.
Funding Information
  • grants-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan (10670462)
  • Research Group of Intractable Liver Diseases, sponsored by the Ministry of Health and Welfare of Japan