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Interferon gamma (IFN-γ) is a key factor in the protection of hosts against intracellular parasites. This cytokine induces parasite killing through nitric oxide and reactive oxygen species production by phagocytes. Surprisingly, during Leishmania amazonensis infection, IFN-γ plays controversial roles. During in vitro infections, IFN-γ induces the proliferation of the amastigote forms of L. amazonensis. However, this cytokine is not essential at the beginning of an in vivo infection. It is not clear why IFN-γ does not mediate protection during the early stages of infection. Thus, the aim of our study was to investigate the role of IFN-γ during L. amazonensis infection. We infected IFN-γ−/− mice in the footpad and followed the development of leishmaniasis in these mice compared with that in WT mice. CD4+ T lymphocytes and macrophages migrated earlier to the site of infection in the WT mice, and the earlier migration of these 2 cell types was associated with lesion development and parasite growth, respectively. These differences in the infiltrate populations were explained by the increased expression of chemokines in the lesions of the WT mice. Thus, we propose that IFN-γ plays a dual role during L. amazonensis infection; it is an important inducer of effector mechanisms, particularly through inducible nitric oxide synthase expression, and conversely, it is a mediator of inflammation and pathogenesis through the induction of the expression of chemokines. Our data provided evidence for a pathogenic effect of IFN-γ production during leishmaniasis that was previously unknown. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to assess the effect of arginine supplementation on arginase activity, tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) synthesis in cultured splenic macrophages from a murine model of intestinal obstruction (IO). The effects of nitric oxide synthase (iNOS) inhibition were also studied using iNOS knockout animals., Material and Methods: Male C57BL6/J wild-type (WT) and iNOS knockout (iNOS-/-) mice were randomized into 6 groups: Sham and Sham-/- (standard chow), IO and IO-/- (standard chow + IO), and Arg and Arg-/- (standard chow supplemented with arginine + IO). After 7 days of treatment with standard or supplemented chow, IO was induced. Arginase activity as well as TNF-α and IL-10 levels were analyzed in splenic macrophage cultures., Results: Arginine supplementation and the absence of iNOS increased arginase activity in splenic macrophages (Arg, IO-/-, and Arg-/- groups vs the Sham group; P < .05). Arginine was also related to a decrease in TNF-α levels (Arg vs IO group, P < .05) and maintenance of IL-10 levels (Arg vs other groups, P > .05). The inhibition of iNOS did not result in effects on the concentration of cytokines (Sham-/-, IO-/-, and Arg-/- vs other, P < .05)., Conclusions: Arginine supplementation and iNOS inhibition led to increased arginase activity. Arginine availability decreased plasma TNF-α levels, which may be directly related to nitric oxide derived from arginine., (© 2014 American Society for Parenteral and Enteral Nutrition.)

Interferon gamma (IFN-γ) is a key factor in the protection of hosts against intracellular parasites. This cytokine induces parasite killing through nitric oxide and reactive oxygen species production by phagocytes. Surprisingly, during Leishmania amazonensis infection, IFN-γ plays controversial roles. During in vitro infections, IFN-γ induces the proliferation of the amastigote forms of L. amazonensis. However, this cytokine is not essential at the beginning of an in vivo infection. It is not clear why IFN-γ does not mediate protection during the early stages of infection. Thus, the aim of our study was to investigate the role of IFN-γ during L. amazonensis infection. We infected IFN-γ(-/-) mice in the footpad and followed the development of leishmaniasis in these mice compared with that in WT mice. CD4(+) T lymphocytes and macrophages migrated earlier to the site of infection in the WT mice, and the earlier migration of these 2 cell types was associated with lesion development and parasite growth, respectively. These differences in the infiltrate populations were explained by the increased expression of chemokines in the lesions of the WT mice. Thus, we propose that IFN-γ plays a dual role during L. amazonensis infection; it is an important inducer of effector mechanisms, particularly through inducible nitric oxide synthase expression, and conversely, it is a mediator of inflammation and pathogenesis through the induction of the expression of chemokines. Our data provided evidence for a pathogenic effect of IFN-γ production during leishmaniasis that was previously unknown.

A model of skin infection with Leishmania amazonensis with low doses of parasites is compared to infection with high doses of L. amazonensis and low and high doses of Leishmania major. C57BL/6 mice were infected with 10³ or 10(6) parasites in the ear and the outcome of infection was assessed. The appearance of lesions in mice infected with 10³ parasites was delayed compared to mice infected with 10(6) Leishmania and parasites were detectable at the infection site before lesions became apparent. Mice infected with L. amazonensis displayed persistent lesions, whereas infection with L. major spontaneously healed in all groups, although lymphocytes persisted at the site of infection after healing. Macrophages persisted only in L. amazonensis-infected mice. High-dose L. amazonensis-infected mice produced lower levels of IFN-γ and TNF than mice infected with L. major. No correlation between the persistence of parasites and IL-10 levels and the production of nitric oxide or urea by macrophages was found. We conclude that infection with low doses of L. amazonensis in the dermis changes the course of infection by delaying the appearance of lesions. However, low-dose infection does not change the outcomes of susceptibility and cytokine production described for subcutaneous infection with high numbers of parasites.