Autoamplification of apoptosis following ligation of CD95-L, TRAIL and TNF-α

Abstract

CD95-L, TNF-α and TRAIL are death-inducing ligands (DILs) which may signal apoptosis via crosslinking of their cognate receptors. The present study shows that treatment of cells with agonistic mAB αAPO-1 (CD95), recombinant TRAIL or TNF-α leads to enhanced mRNA and protein expression of each DIL with concomitant death in target cells. Immunoprecipitation of CD95-L protein from supernatant as well as neutralizing antibodies suggest DIL proteins to be cooperatively acting mediators of these cytotoxic activity. Autoamplification of the death signal was blocked in cells with a defect in apoptosis signaling either due to a dysfunctional FADD molecule or to the failure to activate JNK/SAPKs. Phosphorylation and enhanced binding of cJun and ATF-2 to DIL promoters suggest JNK/SAPKs as activators of these transcription factors following death receptor triggering. In consequence, autocrine production of DILs allows the spread of death signals to sensitive target cells.