Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine

Abstract

Peritoneal macrophages from CBA mice incubated with rIFN-gamma are effective in killing the protozoal parasite Leishmania major in vitro. This leishmanicidal activity can be completely inhibited by L-NG-monomethyl arginine (L-NMMA), a specific inhibitor of the L-arginine:nitric oxide (NO) pathway. The culture supernatants of macrophage activated by IFN-gamma contain increased levels of NO2-, the production of which is inhibited by L-NMMA, but not by its D-enantiomer. L. major promastigotes are killed when incubated at room temperature in PBS containing NO. These data demonstrate that NO is an effector mechanism in macrophage killing of intracellular protozoa. The importance of NO in vivo is demonstrated by the finding that CBA mice infected with L. major developed exacerbated disease when L-NMMA was injected into the lesions, resulting in 10(4)-fold increases in the number of parasites extractable from the lesions.