MULTIPLE PATHWAYS OF FAS-INDUCED APOPTOSIS IN PRIMARY CULTURE OF HEPATOCYTES

Fas (Apo1/CD95) is a member of the tumour necrosis factor/nerve growth factor receptor superfamily and mediates apoptosis in various cell ty pes (for review see [1]). Although this apoptotic activity has been cl early related to homeostasis in the immune system and pathological sit uations in non-lymphoid organs, the Fas signaling pathway remains most ly elusive. We and others previously showed that Fas-induced apoptosis of primary culture hepatocytes requires either an inhibitor of transl ation or a protein kinase inhibitor, suggesting that two distinct path ways of Fas signaling exist in hepatocytes. We report here that activa tion of ICE-like and CPP32-like cysteine proteases are required for Fa s-mediated apoptosis, but that these pathways involve different subcla sses of serine proteases and are selectively modulated by inhibitors o f protein tyrosine kinases. These results confirm that distinct pathwa ys can lead to Fas-induced apoptosis in hepatocytes. Further understan ding of these pathways could facilitate the rational design of anti-ap optotic drags in liver diseases associated with massive Fas-mediated h epatocyte apoptosis, including fulminant hepatitis. (C) 1996 Academic Press, Inc.