INVOLVEMENT OF THE CD95 (APO-1 FAS) RECEPTOR AND LIGAND IN LIVER-DAMAGE/

Apoptosis occurs in the normal liver and in various forms of liver dis ease. The CD95 (APO-1/Fas) (CD95) receptor mediates apoptosis, and liv er cells in animal models are acutely sensitive to apoptosis initiated by this receptor. We have used primary human hepatocytes as a model s ystem to investigate CD95-mediated apoptotic liver damage. Treatment o f fresh human hepatocytes with low concentrations of agonistic antibod ies against CD95 resulted in apoptosis of >95% of the cultured liver c ells within 4 and 7.5 h. Immunohistology of a panel of explanted liver tissues revealed that hepatocytes in normal livers (n = 5) and in alc oholic cirrhosis (n = 13) expressed low constitutive levels of CD95. C D95 receptor expression was highly elevated in hepatocytes in hepatiti s B virus-related cirrhosis (n = 9) and in acute liver failure (n = 8) . By in situ hybridization CD95 ligand messenger RNA expression was ab sent in normal liver but detected at high levels in livers with ongoin g Liver damage. In cases of hepatitis B virus-related cirrhosis and ac ute hepatic failure, ligand expression was found primarily in areas wi th lymphocytic infiltration. In contrast, in patients with alcoholic l iver damage, high CD95 Ligand messenger RNA expression was found in he patocytes. These findings suggest that liver destruction in hepatitis B may primarily involve killing of hepatocytes by T lymphocytes using the CD95 receptor-ligand system. In alcoholic liver damage, death of h epatocytes might occur by fratricide and paracrine or autocrine mechan isms mediated by the hepatocytes themselves.