THE 55-KD TUMOR-NECROSIS-FACTOR RECEPTOR AND CD95 INDEPENDENTLY SIGNAL MURINE HEPATOCYTE APOPTOSIS AND SUBSEQUENT LIVER-FAILURE

Background: Activation of either the 55-kD tumor necrosis factor recep tor (TNF-R1) or CD95 (Fas/Apo-1) causes apoptosis of cells and liver f ailure in mice, and has been associated with human liver disorders. Th e aim of this study was first to clarify the association between CD95 activation, hepatocyte apoptosis, and fulminant liver failure. Next, w e investigated whether TNF-R1 and CD95 operate independently of each o ther in the induction of hepatocyte apoptosis. Materials and Methods: Using both mice and primary liver cell cultures deficient in either TN F-R1 or functional CD95, the induction of apoptosis and hepatocyte dea th following activation of TNF-R1 or CD95 were studied in vitro and in various in vivo models of acute liver failure. Results: in vivo or in vitro stimulation of CD95 caused apoptosis of wild-type (wt) murine h epatocytes which had not been sensitized by blocking transcription. Ti me course studies showed that DNA fragmentation and chromatin condensa tion preceded, respectively, membrane lysis in vitro and necrosis in v ivo. Similar results were obtained after CD95 activation in hepatocyte s or livers lacking TNF-R1. Conversely, hepatocytotoxicity due to endo genous or exogenous TNF was not affected in animals or liver cell cult ures lacking the expression of functional CD95. Conclusions: TNF-R1 an d CD95 are independent and differentially regulated triggers of murine apoptotic liver failure.