An in vitro study was performed in order to assess a possible regulatory role of nitric oxide (NO), a short-lived biologic mediator that displays immunoregulatory properties, in the IL-4-driven synthesis of IgE by normal human peripheral blood mononuclear cells (PBMC). In addition to induce IgE production, IL-4 was found to elicit nitrite (NO2-) release by PBMC. A marked correlation was observed between IgE secretion and nitrite release by PBMC stimulated with an optimal concentration of IL-4. The IL-4-dependent IgE production was significantly reduced (p < 0.001) in the presence of N omega-monomethyl-L-arginine (LNMMA), an inhibitor of the NO-synthase pathway; this inhibition was partially reverted with an excess of L-arginine. Addition to PBMC cultures of the chemical NO donor Sin-1, inactive alone, was found to result, depending on the concentration of IL-4, in either potentiation (suboptimal concentration of IL-4, 10 ng/ml) or inhibition (optimal concentration of IL-4, 50 ng/ml) of IgE synthesis. The potentiating effect of Sin-1 was dose dependent, with a maximal effect for 300 microM, whereas its metabolite Sin-1c was inactive. In both cases, Sin-1 markedly reduced the IL-4-induced release of the soluble form of the low affinity IgE receptor (sCD23). Together, these data strongly suggest that NO may display biphasic immunoregulatory properties on the IL-4-induced IgE production by PBMC.