N

N. cytokines most associated with nonhealing forms of leishmaniasis are interleukin 4 (IL-4) and IL-10. For example, infection in BALB/c mice results in nonhealing disease associated with high levels of IL-4, and neutralizing IL-4 can promote resistance (21). IL-10 also contributes to susceptibility in BALB/c mice and also modulates protective immune responses in B6 mice infected with (8, 27, 37). In contrast, BI-78D3 that also causes chronic disease in B6 mice, still causes chronic infection of IL-4- and IL-10-deficient mice (24, 25). However, while previous studies indicate that IL-4 and IL-13 may contribute to the chronicity of infections (3, 45), the role of IL-10 in the chronic disease induced by in B6 mice has not been investigated. The immune responses associated with infection are distinct from those observed following infection with infection of B6 mice induces a significant immune response, characterized by increased cell migration to the draining lymph node (LN), proliferation of or is limited. Notably, mouse strains resistant to not only fail to develop a dominant Th1 response when infected with these New World parasite species, they also show no evidence of a strong Th2 response (1, 45). Furthermore, in contrast to lesions, lesions from infections may not be linked with a Th2 response but rather WT1 is more likely the result of generalized immunosuppression mediated by IL-10. Studies with infectious diseases and models of autoimmunity indicate that the regulatory role of IL-10 can be vital to blocking immunopathologic responses. For example, infections of IL-10-deficient mice with and result in fatal inflammatory responses (15, 32), and similarly, IL-10-deficient mice have spontaneous autoimmune colitis (31) and more severe experimental autoimmune encephalomyelitis (10, 44). These models demonstrate that IL-10 can play a critical protective role against immunopathology. Interestingly, however, there is no BI-78D3 evidence that IL-10?/? mice infected with lesions produced high levels of IL-10 when stimulated in vitro with parasites opsonized with antibody were capable of augmenting lipopolysaccharide (LPS)-induced IL-10 production by macrophages in an FcR-dependent manner (27). The role of IL-10, FcR, and immunoglobulin G (IgG) in leading to susceptibility to infections of B6 mice by New World species, such as and in B6 mice (8) and is required for progressive disease in the much more susceptible BALB/c strain (27). In BALB/c mice, which are also much more susceptible than B6 mice to and other New World strains, IL-10 contributes to susceptibility to and (29), but this has not been linked with IL-10 production. In addition, B6 IL-10?/? mice do not heal infections despite an increase in IFN- at early time points (24). Thus, the roles of IL-10, FcR, and IgG in infection are by no means understood, even in BALB/c mice, and BI-78D3 have not been investigated in the relatively more resistant B6 mice, whose disease with both and more closely resembles human leishmaniasis. In the present study, we demonstrate that in the absence of IL-10, B6 mice are able to resolve infections. Resolution of infection was also observed in mice lacking FcR and circulating IgG, which implicates macrophagesstimulated through the FcR by IgG-opsonized parasitesas a critical source of IL-10. Consistent with this hypothesis, we demonstrate that IgG bound to the surface of promotes the induction of IL-10 from B6 macrophages in vitro. We further show that LN cells from in B6 mice and also BI-78D3 to uncover a critical role BI-78D3 for antibodies, through FcR binding, in this suppression. MATERIALS AND METHODS Mice. B6, B6 IL-4?/?, B6 IL-10?/?, and B6 2-microglobulin (2m)?/? mice were purchased from Jackson Laboratory (Bar Harbor, Maine). B6 FcR?/? and B6 control mice were purchased from Taconic (Germantown, N.Y.). Courses of infection consisted of groups of five mice per experiment, and rechallenge was performed on two to five mice per group. Mice were purchased at 4 to 6 6 weeks and were sex and age matched for all experiments. Animals were maintained in a specific-pathogen-free environment, and the animal colony was screened regularly, and tested negative, for the presence of murine pathogens..