title: Enhancing effect of oxygen radical scavengers on murine macrophage anticryptococcal activity through production of nitric oxide.
abstract: We examined the roles of reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI) in interferon-gamma (IFN-gamma)-induced cryptococcostatic activity of murine peritoneal macrophages using N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of RNI synthesis, and superoxide dismutase (SOD) and catalase, oxygen radical scavengers. IFN-gamma-activated macrophages produced nitric oxide (NO) in a dose-dependent manner, as measured by increased nitrite concentration in the culture supernatant. IFN-gamma also enhanced the suppressive effect on cryptococcal growth in a similar dose-dependent manner. The induction of killing activity and NO production by an optimal dose of IFN-gamma (100 U/ml) was virtually suppressed by 500 microM L-NMMA. These results confirmed the importance of the RNI-mediated effector mechanism in anticryptococcal activity of macrophages. SOD and catalase significantly enhanced the cryptococcostatic activity of macrophages induced by a suboptimal dose of IFN-gamma (20 U/ml). The augmenting effect of these reagents was mediated by NO, since they potentiated the production of NO by macrophages and their effects were totally blocked by L-NMMA. Our results indicate that the IFN-gamma-induced anticryptococcal activity of macrophages is dependent mostly on RNI, and suggest that the ROI system down-regulates the effector mechanism for cryptococcostasis by suppressing the RNI system.
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tohyama
authors.forename: K
authors.initials: K
authors.lastname: Kawakami
authors.forename: M
authors.initials: M
authors.lastname: Futenma
authors.forename: A
authors.initials: A
authors.lastname: Saito
mesh_terms: D000818:Animals; D000908:Antibodies, Fungal / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D003455:Cryptococcus neoformans / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology*; D017672:Nitrogen Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D019323:omega-N-Methylarginine
chemical_list: D000908:Antibodies, Fungal; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017672:Nitrogen Compounds; D017382:Reactive Oxygen Species; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D002374:Catalase; D013482:Superoxide Dismutase