Cryptococcus neoformansInhibits Nitric Oxide Production by Murine Peritoneal Macrophages Stimulated with Interferon-γ and Lipopolysaccharide

We examined the effect ofCryptococcus neoformanson nitric oxide (NO) production by activated cultured macrophages.C. neoformanssuppressed NO production by murine peritoneal macrophages stimulated with bacterial lipopolysaccharide (LPS) and interferon (IFN)-γ, while it did not influence the production of IL-1β. This effect was observed when 1 × 106or 107ofC. neoformanswas added to macrophage cultures. A direct contact ofC. neoformanswith macrophages was essential for this inhibitory effect, since placement of a 0.45-μm-pore membrane between the organism and macrophages prevented such effect. In addition,C. neoformanskilled by heat or paraformaldehyde did not show this inhibitory activity. Capsular polysaccharide did not mediate the inhibitory effect, since two nonencapsulated mutant strains ofC. neoformansshowed an inhibitory activity similar to that of encapsulated wild strains, and culture supernatants ofC. neoformans,rich in polysaccharide antigens, did not inhibit macrophage NO production compared with control culture medium. The inhibitory effect was also not mediated by interleukin (IL)-10 and transforming growth factor (TGF)-β since neutralizing specific antibodies to these cytokines did not influenceC. neoformans-induced reductions in macrophage NO production. Our results suggest thatC. neoformansmay cause a direct suppression of NO-mediated fungicidal activity of macrophages, and the effect is independent of the capsular polysaccharide and production of IL-10 and TGF-β.