ANTICRYPTOCOCCAL EFFECT OF AMPHOTERICIN-B IS MEDIATED THROUGH MACROPHAGE PRODUCTION OF NITRIC-OXIDE

Amphotericin B (AmB) is a classical antifungal drug and one of the mos t effective antifungal drugs for the treatment of systemic fungal infe ction. It is also known to have various immunomodulating activities ot her than its direct antifungal effect. In the present study, we demons trated that AmB augmented gamma interferon (IFN-gamma)-induced killing potentials of murine peritoneal macrophages against Cryptococcus neof ormans in a dose-dependent manner, This effect was strongly blocked by N-G-monomethyl-L-arginine, a competitive inhibitor of nitric oxide (N O) synthesis. In addition, AmB markedly augmented macrophage NO produc tion induced by IFN-gamma with a dose-response curve similar to that s een with its effect on the anticryptococcal activity, These effects we re partially mediated by either tumor necrosis factor alpha or interle ukin-l, because AmB enhanced IFN-gamma-induced production of these cyt okines by macrophages and their specific antibodies partially inhibite d the AmB-induced enhancement of NO generation when they were used sep arately. Our results indicate that AmB induces the production of tumor necrosis factor alpha and IL-1 by macrophages and augments their anti cryptococcal activity through triggering the NO-dependent pathway.