Antihistoplasma effect of activated mouse splenic macrophages involves production of reactive nitrogen intermediates.
The mechanism by which recombinant murine gamma interferon (rMuIFN-gamma) and bacterial lipopolysaccharide (LPS) activate mouse resident splenic macrophages to inhibit the intracellular growth of the fungus Histoplasma capsulatum was examined. Growth inhibition depended on L-arginine metabolism. The growth inhibitory state normally induced by rMuIFN-gamma and LPS in resident splenic macrophages did not occur when the macrophages were cultured in the presence of NG-monomethyl-L-arginine, 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 cultured in the presence of NG-monomethyl-L-arginine together with rMuIFN-gamma and LPS, only baseline levels of NO2- were detected. Spleen cells from H. capsulatum-infected mice produced high levels of NO2- in culture. The production of NO2- correlated with in vitro inhibition of the intracellular growth of H. capsulatum. Anti-tumor necrosis factor alpha antibody did not block NO2- production by the immigrant splenic macrophages and did not abolish the antihistoplasma activity.
Lane
T E
TE
Department of Microbiology and Immunology, University of California, Los Angeles, School of Medicine 90024.
Wu-Hsieh
B A
BA
Howard
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DH
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006658:Histoplasma / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009573:Nitrites / Q000378:metabolism*; D011994:Recombinant Proteins; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D019323:omega-N-Methylarginine
D009573:Nitrites; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; D007371:Interferon-gamma; D001120:Arginine