Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP

Cross-linking of the B cell antigen receptor (BCR) induces resistance to Fa s (APO-1/CD95)-dependent apoptosis and thereby regulates one mechanism of B cell selection during antigen stimulation. To investigate the molecular me chanism by which BCR signaling regulates the Fas pathway, we examined the e xpression of constituents of the death inducing signaling complex (DISC), i ncluding Fas, FADD, caspase-8 and cellular FLICE-inhibitory protein (c-FLIP ). No significant changes in the cellular levels of Fas, FADD or caspase-8 were observed after BCR cross-linking. By contrast, the long isoform of c-F LIP (c-FLIPL) was significantly up-regulated by BCR cross-linking in primar y B cells and in two B cell lines, A20 and WEHI-279. Moreover, transfection of c-FLIPL into A20 cells inhibited Fas-dependent apoptosis and suppressed recruitment of caspase-8 to the DISC. BCR cross-linking or FLIP overexpres sion also protects B cells from TRAIL-induced apoptosis. Thus, BCR signalin g up-regulates c-FLIPL and suppresses the Fas- and TRAIL-receptor apoptosis pathways which could be important for tolerance and selection of antigen-s pecific B cells.