Cytokines secreted by IL-2-activated lymphocytes induce endogenous nitric oxide synthesis and apoptosis in macrophages.

IL-2-activated killer (LAK) cells secrete inflammatory cytokines such as IFN-gamma and TNF-alpha, which can induce NO synthesis (NOS). In this study, we investigated IL-2-activated lymphocyte-mediated macrophage apoptosis via NOS. LAK cells and their culture supernatants induced NOS in murine macrophages. NOS was markedly inhibited by blocking antibodies to IFN-gamma and TNF-alpha, suggesting the key role of these lymphocyte cytokines in mediating NOS. Endogenous NO production inhibited macrophage proliferation and induced apoptosis in concordance with p53 accumulation and caspase-3 activation, processes that were inhibited by N(G)-monomethyl-l-arginine (a NOS inhibitor) and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (a NO scavenger). Our study demonstrated a novel, noncontact-dependent mechanism of macrophage suppression by IL-2-activated lymphocytes: induction of growth inhibition and apoptosis of macrophages as a result of endogenous NOS induced by cytokines secreted from IL-2-activated lymphocytes.