PREEXPOSURE OF MURINE MACROPHAGES TO LIPOPOLYSACCHARIDE INHIBITS THE INDUCTION OF NITRIC-OXIDE SYNTHASE AND REDUCES LEISHMANICIDAL ACTIVITY

Murine macrophages produce nitric oxide (NO) from L-arginine on stimul ation with lipopolysaccharide (LPS), alone or with interferon-gamma (I FN-gamma). The effect of incubation of macrophages with low concentrat ions of LPS on NO synthesis on subsequent stimulation was investigated , using a murine macrophage cell line, J774, and peritoneal macrophage s from CBA mice. Cells which had been incubated with LPS produced sign ificantly lower amounts of NO, and expressed lower levels of NO syntha se activity, following stimulation with IFN-gamma and LPS, or with a h igh concentration of LPS. This effect was not reversed by tumor necros is factor-alpha. The ability of CBA macrophages to kill the intracellu lar parasite Leishmania major was markedly reduced by pre-incubation w ith LPS. Reduced NO production by macrophages previously exposed to LP S is a manifestation of endotoxin tolerance, and may represent an impo rtant means of regulation of NO synthesis and thus a survival mechanis m for intracellular parasites.