TUMOR-NECROSIS-FACTOR RECEPTOR P55 IS ESSENTIAL FOR INTRAHEPATIC GRANULOMA-FORMATION AND HEPATOCELLULAR APOPTOSIS IN A MURINE MODEL OF BACTERIUM-INDUCED FULMINANT-HEPATITIS

Accumulating evidence implicates tumor necrosis factor (TNF) and Pas s ystems in liver injury, although the interaction between these two sys tems remains to be investigated, In this study, we examined Propioniba cterium acnes-primed TNF receptor p55-deficient (TNFRp55(-/-)) or Fas- deficient MRL/MpJ Lpr/Lpr mice challenged with lipopolysaccharide (LPS ), Priming with P. acnes caused mononuclear cell infiltration into the hepatic lobules and granuloma formation in the livers of TNFRp55 wild -type mice, Subsequent LPS challenge caused massive liver injury and a marked increase in transaminase levels, leading to acute lethality in control. wild-type mice, In contrast, the same treatment caused few p athological changes in livers of TNFRp55 mice, and all animals survive d. P. acues and subsequent LPS challenge induced granuloma formation a nd apoptotic changes, respectively, in livers of MRL/MpJ Lpr/Lpr mice, However, liver injury was 50% of that in control MRL/MpJ +/+ mice, su ggesting some role of the Fas-Fas ligand system in this liver injury m odel, On the other hand, an agonistic anti-Fas antibody caused massive apoptosis and hemorrhagic changes of the liver without any priming wi th P. acnes, leading to death in both TNFRp55(-/-) and control wild-ty pe mice, These results suggest that TNFRp55 but not Pas was involved i n P. acnes-induced granuloma formation as well as subsequent LPS-induc ed liver injury and that TNFRp55 and Pas independently induced apoptos is of hepatocytes in vivo.