Following infection with the protozoan parasite Leishmania major, C57BL/6 mice develop a small lesion that heals spontaneously. Resistance to infection is associated with the development of CD4 ؉ Th1 cells producing gamma interferon (IFN-␥) and tumor necrosis factor (TNF), which synergize in activating macrophages to their microbicidal state. We show here that C57BL/6 mice lacking both TNF and Fas ligand (FasL) (gld TNF ؊/؊ mice) infected with L. major neither resolved their lesions nor controlled Leishmania replication despite the development of a strong Th1 response. Comparable inducible nitric oxide synthase (iNOS) activities were detected in lesions of TNF ؊/؊ , gld TNF ؊/؊ , and gld mice, but only gld and gld TNF ؊/؊ mice failed to control parasite replication. Parasite numbers were high in gld mice and even more elevated in gld TNF ؊/؊ mice, suggesting that, in addition to iNOS, the Fas/FasL pathway is required for successful control of parasite replication and that TNF contributes only a small part to this process. Furthermore, FasL was shown to synergize with IFN-␥ for the induction of leishmanicidal activity within macrophages infected with L. major in vitro. Interestingly, TNF ؊/؊ mice maintained large lesion size throughout infection, despite being able to largely control parasite numbers. Thus, IFN-␥, FasL, and iNOS appear to be essential for the complete control of parasite replication, while the contribution of TNF is more important in controlling inflammation at the site of parasite inoculation.In the experimental murine model of infection with the intracellular protozoan Leishmania major, susceptibility to infection has been correlated with the development of lesions associated with a Th2 type of immune response, while healing of lesions in resistant mice has been correlated with the development of a Th1 type of immune response (reviewed in reference 27). The resolution of lesions has been shown to involve several factors contributing to the killing of L. major within macrophages. The most efficient mechanism of parasite destruction involves the production of gamma interferon (IFN-␥) by CD4 ϩ Th1 cells, which induces the synthesis of inducible nitric oxide synthase (iNOS), generating the production of reactive nitrogen radicals toxic for the intracellular parasite (reviewed in reference 4). Tumor necrosis factor (TNF) has also been shown to be involved in parasite killing in a process that depends on NO production, and endogenously produced TNF has been reported to be necessary for NO production by macrophages in vitro (3,12,17,33).The importance of TNF in the control of infection with Leishmania has been studied extensively, but its exact role remains unclear. Mice resistant to infection with L. major were shown to produce significant amounts of TNF in their draining lymph nodes during the course of infection, while no TNF was detectable in susceptible animals (35). Injections of recombinant human TNF (rhTNF) into either resistant or susceptible strains of mice had a therapeutic effect on the co...
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