CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily

CD40 a tumor necrosis factor (TNF) receptor (TNFR) family member, conveys s ignals regulating diverse cellular responses? ranging from proliferation an d differentiation to growth suppression and cell death. The ability of CD-I O to mediate apoptosis in carcinoma cells is intriguing given the fact that the CD40 cytoplasmic C terminus lacks a death domain homology with the cyt otoxic members of the TNFR superfamily, such as Fas, TNFR1, and TNF-related apoptosis-inducing ligand (TRAIL) receptors, In this study, me have probed the mechanism by which CD40 transduces death signals. Using a trimeric rec ombinant soluble CD40 ligand to activate CD-40, we have found that this phe nomenon critically depends on the membrane proximal domain (amino acids 216 to 239) but not the TNFR-associated factor-interacting PXQXT motif in the CD40 cytoplasmic tail. CD40-mediated cytotoxicity is blocked by caspase inh ibitors, such as zVAD-fmk and crmA, and involves activation of caspase 8 an d caspase 3, Interestingly, CD40 ligation was found to induce functional Fa s ligand, TRAIL (Apo-2L) and TNF in apoptosis-susceptible carcinoma cells a nd to up-regulate expression of Fas, These findings identify a novel proapo ptotic mechanism which is induced by CD40 in carcinoma cells and depends on the endogenous production of cytotoxic cytokines and autocrine or paracrin e induction of cell death.