ANTIHISTOPLASMA EFFECT OF ACTIVATED MOUSE SPLENIC MACROPHAGES INVOLVES PRODUCTION OF REACTIVE NITROGEN INTERMEDIATES

The mechanism by which recombinant murine gamma interferon (rMuIFN-gam ma) and bacterial lipopolysaccharide (LPS) activate mouse resident spl enic macrophages to inhibit the intracellular growth of the fungus His toplasma capsulatum was examined. Growth inhibition depended on L-argi nine metabolism. The growth inhibitory state normally induced by rMuIF N-gamma and LPS in resident splenic macrophages did not occur when the macrophages were cultured in the presence of N-G-monomethyl-L-arginin e, a competitive inhibitor of L-arginine metabolism. Resident splenic macrophages treated with rMuIFN-gamma and LPS produced nitrite (NO2-), an end product of L-arginine metabolism. When macrophages were cultur ed in the presence of N-G-monomethyl-L-arginine together with rMuIFN-g amma and LPS, only baseline levels of NO2- were detected. Spleen cells from H. capsulatum-infected mice produced high levels of NO2- in cult ure. The production of NO2- correlated with in vitro inhibition of the intracellular growth of H. capsulatum. Anti-tumor necrosis factor alp ha antibody did not block NO2- production by the immigrant splenic mac rophages and did not abolish the antihistoplasma activity.