CELLULAR MECHANISMS OF NONSPECIFIC IMMUNITY TO INTRACELLULAR INFECTION - CYTOKINE-INDUCED SYNTHESIS OF TOXIC NITROGEN-OXIDES FROM L-ARGININE BY MACROPHAGES AND HEPATOCYTES

Nitric oxide (NO) produced by cytokine-treated macrophages and hepatocytes plays a vital role in protective host responses to infectious pathogens. NO inhibits iron-sulfur-dependent enzymes involved in cellular respiration, energy production, and reproduction. Synthesis of l-arginine-derived nitrite (NO2-), the oxidative end product of NO, directly correlates with intracellular killing of Leishmania major, an obligate intracellular protozoan parasite of macrophages: the level of NO2- production is a quantitative index for macrophage activation. The competitive inhibitor of NO synthesis, monomethylarginine (NGMMLA), inhibits both parasite killing and NO2- production. For Leishmania, the parasite itself participates in the regulation of this toxic effector mechanism. This participation is mediated by parasite induction of tumor necrosis factor α (TNFα), an autocrine factor of macrophages: NO synthesis by interferon-γ (IFN-γ)-treated cells can be blocked by monoclonal antibodies to TNFα. NO production by IFNγ-treated hepatocytes is of special interest in malaria infections: sporozoite-infected hepatocytes kill the intracellular malaria parasite after treatment with IFNγ; this killing is inhibited by NGMMLA. © 1990.