S-ADENOSYLHOMOCYSTEINE AS A PHYSIOLOGICAL MODULATOR OF APO-1-MEDIATEDAPOPTOSIS

APO-1/Fas (CD95) is a member of the tumor necrosis factor/nerve growth factor receptor superfamily and mediates apoptosis in various cell ty pes. Here we show that L929 cells, expressing human APO-1 treated with agonistic antibodies (anti-APO-l), elicit an early and transient incr ease of S-adenosylhomocysteine (AdoHcy), a potent inhibitor of S-adeno sylmethionine (AdoMet)-dependent methylation reactions. In contrast, a nti-APO-1 did not induce an AdoHcy increase in L929-APO-1 Delta 4 cell s expressing a C-terminally truncated APO-1 lacking part of the 'death domain' known to be required for the transduction of apoptotic signal s. Addition of adenosine and D,L-homocysteine also led to an increase of cellular AdoHcy thus enhancing anti-APO-1-induced killing of L929-A PO-1 cells. Treatment with anti-APO-1 also induced release of arachido nic acid from phospholipids: this effect was augmented by elevated lev els of AdoHcy. In contrast, AdoHcy had only a minor effect on anti-APO -1 anti-APO-1-mediated DNA fragmentation. These findings suggest that AdoHcy functions as a physiological modulator of APO-l-mediated cell d eath in L929 cells and enhances anti-APO-l-induced cell killing at lea st partially by acting via the phospholipase A(2) pathway.