Nitric oxide: Cytokine-regulation of nitric oxide in host resistance to intracellular pathogens

Abstract

To discover how nitric oxide (NO) synthesis is controlled in different tissues as cells within these tissues combat intracellular pathogens, we examined three distinctively different experimental murine models designed for studying parasite-host interactions: macrophage killing of Leishmania major; nonspecific protection against tularemia (Francisella tularensis) by Mycobacterium bovis (BCG); and specific vaccine-induced protection against hepatic malaria with Plasmodium berghei. Each model parasite and host system provides information on the source and role of NO during infection and the factors that induce or inhibit its production. The in vitro assay for macrophage antimicrobial activity against L. major identified cytokines involved in regulating NO-mediated killing of this intracellular protozoan. L. major induced the production of two competing cytokines in infected macrophages: (1) the parasite activated the gene for tumor necrosis factor (TNF), and production of TNF protein was enhanced by the presence of interferon-gamma (IFN-[gamma]). TNF then acted as a autocrine signal to amplify IFN-[gamma]-induced production of NO; and (2) the parasite upregulated production of transforming growth factor-beta (TGF-[beta]), which blocked IFN-[gamma]-induced production of NO. Whether parasite-induced TNF (parasite destruction) or TGF-[beta] (parasite survival) prevailed depended upon the presence and quantity of IFN-[gamma] at the time of infection. The relationship between NO production in vivo and host resistance to infection was demonstrated with M. bovis (BCG). These studies confirmed that both IFN-[gamma] and TNF are required for induction of NO-mediated nonspecific host defense in vivo. The presumed source of NO in these studies was the activated macrophage, however, other cells infected with parasites can also be stimulated to produce NO. In studying acquired immunity to malaria induced by irradiated sporozoites, we found that IFN-[gamma] provided by malaria-specific CD8+ T cells stimulated sporozoite-infected hepatocytes to produce NO for destruction of either infected hepatocytes or the parasite, P. berghei, within these cells.