EVIDENCE FOR THE INVOLVEMENT OF MACROPHAGE-DERIVED NITRIC-OXIDE IN THE MODULATION OF IMMUNE STATUS BY A CONDITIONED AVERSIVE STIMULUS

Prior work in our laboratory has demonstrated that exposure to a conditioned aversive stimulus developed through pairings with electric shock results in pronounced alterations of immune status. These conditioned alterations of immune status include a decrease in natural killer cell activity, decreased production of interleukin-2 and gamma-interferon by concanavalin A (ConA)-stimulated splenocytes and a profound suppression of the mitogenic responsiveness of T and B lymphocytes to mitogens. The present study examines the role of macrophage-derived nitric oxide in the conditioned stimulus-induced suppression of lymphocyte proliferation by measuring the level of nitrite accumulation in culture, determining the effect of macrophage depletion, and assessing the effect of N-G-monomethyl-L-arginine (L-NMMA), a specific inhibitor of the L-arginine-dependent nitric-oxide synthesizing pathway, alone and in combination with L- or D-arginine. The results show that the conditioned suppression of the mitogenic responsiveness of splenocytes to ConA is accompanied by a marked increase in nitrite accumulation. Both the depletion of macrophages and the addition of L-NMMA attenuates the conditioned suppression of ConA-stimulated lymphocyte proliferation. Furthermore, the addition of excess L-arginine, but not D-arginine, counteracts the effect of L-NMMA. The present findings show that the neuroendocrine alterations induced by a conditioned aversive stimulus suppress lymphocyte proliferation through alteration of the production of nitric oxide by macrophages.