HUMAN HEPATOCYTES PRODUCE AN ISOFORM OF FAS THAT INHIBITS APOPTOSIS

Background. Fas (Apo-1/CDgB), a member of the tumor necrosis factor re ceptor family, can mediate apoptosis when engaged by its ligand or by anti-Fas antibody, Fas is expressed by cells of the immune system and by some nonlymphoid tissues. Numerous studies have suggested that the Fas pathway may play a role in the rejection of allografts, Functional , soluble forms of the Fas receptor are produced by activated peripher al blood mononuclear cells and some transformed cell lines, The purpos e of this study was to determine if soluble variants of Fas are produc ed in the liver and to determine if blockade of the Fas pathway, by li ver-derived soluble Fas, inhibits Fas-mediated apoptosis, Methods. Liv er and purified hepatocyte specimens were analyzed for Fas transcripts by reverse transcriptase-polymerase chain reaction with primers that span the transmembrane region of the molecule, Bile and cell lysates w ere analyzed for soluble Fas by specific enzyme-linked immunosorbent a ssay, Lysates were prepared from normal liver and hepatocytes and util ized to block Fas-mediated apoptosis of Jurkat cells as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometry, Results, A variant form of Fas is abundantly expre ssed in normal liver and purified hepatocytes, This variant form of Fa s is expressed in all normal liver specimens but only in half of the l iver specimens obtained during allograft rejection. The levels of solu ble Fas diminish in patients undergoing liver allograft rejection in c ontrast to patients with stable grafts, Importantly, a soluble form of Fas is produced in the liver by hepatocytes and can specifically inhi bit Fas-mediated apoptosis, Conclusion, These data raise the possibili ty that soluble Fas, produced by hepatocytes, may influence the immune response by blocking Fas-mediated apoptosis and, thus, may have a rol e in liver transplantation.