Nitric oxide-mediated inhibition of caspase-dependent T lymphocyte proliferation.

Nitric oxide (NO), a pleiotropic signaling molecule produced at sites of inflammation, is a powerful inhibitor of lymphocyte proliferation. Caspases, central effector proteases in apoptosis, have recently been implicated as critical mediators of T cell activation. We and others have shown that NO can inhibit caspases by S-nitrosylation, which is reversible by the reducing agent dithiothreitol (DTT). The purpose of the present study was to determine whether NO inhibits lymphocyte proliferation by modulating caspase activity. Caspase inhibition with z-VAD-fmk blocked T cell proliferation. NO-dependent inhibition of T cell proliferation was associated with an inhibition of caspase activity and activation, and this effect was reversible by DTT. Previous studies demonstrated inhibition of apoptosis through S-nitrosylation of caspases; the present studies extend this effect to inhibition of caspase-dependent T cell proliferation.