Nitric oxide inhibits apoptosis via AP-1-dependent CD95L transactivation

Several inducers of cytotoxic stress promote apoptotic cell death, which, a t least in some cases, involves the CD95/CD95 ligand (CD95L) pathway. The i nduction of the CD95/CD95L pathway can be activated by the activator protei n-1 (AP-l)-mediated up-regulation of the CD95L promoter, which is responsib le for the induction of apoptosis elicited by stimuli such as etoposide. We show that nitric oxide (NO) represents a regulatory element able to block apoptosis hy interfering with this loop. Etoposide- and C6-ceramide-induced apoptosis in Jurkat T cells with different kinetics. Cell death was accomp anied by an increase in DNA-binding activity of the transcription factor AP -1, transactivation of the AP-1 site-containing CD95L promoter, and caspase 3-like protease activation. Using different NO-releasing compounds, we fou nd that apoptosis was prevented in a dose-dependent manner. Furthermore, in both models of apoptosis, NO-releasing compounds dose-dependently reduced: (a) the number of the titratable thiol groups (cysteine residues) of c-Jun ; (b) induction of AP-1 DNA-binding activity; (c) AP-l-driven transactivati on of the CD95L promoter; and (d) caspase activation. In conclusion, our da ta demonstrate that NO can modulate cell death at an upstream level, by int erfering with the ability of AP-I to induce CD95L expression.