APOPTOTIC SIGNAL OF FAS IS NOT MEDIATED BY CERAMIDE

Ceramide has been suggested as the secondary messenger mediating the a poptotic signal for Fas engagement. By using different inhibitors, we demonstrated here that ceramide is unlikely a mediator of Fas-initiate d apoptosis. First, cAMP prevented cell death induced by ceramide but not by Fas. Second, ceramide-triggered but not Fas-triggered, apoptosi s was antagonized by the free radical scavenger C-60. Third, the metal chelator pyrrolidinedithiocarbamate suppressed ceramide-initiated DNA fragmentation but had no effect on the Fas-induced cell death. Fourth , the SAPK/ERK kinase dominant negative mutant, which attenuated ceram ide-induced cell death, did not prevent Fas-induced apoptosis. Finally , activation of NF-kappa B inhibited ceramide-induced but not Fas-init iated apoptosis. The fact that many antagonists of ceramide-induced ap optosis could not suppress Fas-mediated cell death clearly indicates t hat ceramide is not the mediator for Fas-initiated apoptotic signal. ( C) 1998 by The American Society of Hematology.