Protection against progressive leishmaniasis by IFN-beta

Type I IFNs (IFN-alphabeta) exert potent antiviral and immunoregulatory activities during viral infections, but their role in bacterial or protozoan infections is poorly understood. In this study, we demonstrate that the application of low, but not of high doses of IFN-beta protects 60 or 100% of BALB/c mice from progressive cutaneous and fatal visceral disease after infection with a high (10(6)) or low (10(4)) number of Leishmania major parasites, respectively. IFN-beta treatment of BALB/c mice restored the NK cell cytotoxic activity, increased the lymphocyte proliferation, and augmented the production of IFN-gamma and IL-12 in the draining lymph node. Low, but not high doses of IFN-beta caused enhanced tyrosine phosphorylation of STAT1 and STAT4, suppressed the levels of suppressor of cytokine signaling-1, and up-regulated the expression of inducible NO synthase in vivo. The IFN-beta-induced increase of IFN-gamma production was dependent on STAT4. Protection by IFN-beta strictly required the presence of inducible NO synthase. In the absence of STAT4 or IL-12, IFN-beta led to an amelioration of the cutaneous and visceral disease, but was unable to prevent its progression. These results identify IFN-beta as a novel cytokine with a strong, dose-dependent protective effect against progressive cutaneous leishmaniasis that results from IL-12- and STAT4-dependent as well as -independent events.