Abstract
Type 2 nitric oxide synthase (NOS2) is required for the Th1-dependent healing of infections with intracellular microbes, including Leishmania major. Here, we demonstrate the expression and define the function of NOS2 during the innate response to L. major. At day 1 of infection, genetic deletion or functional inactivation of NOS2 abolished the IFNgamma and natural killer cell response, increased the expression of TGFbeta, and caused parasite spreading from the skin and lymph node to the spleen, liver, bone marrow, and lung. Induction of NOS2 was dependent on IFNalpha/beta. Neutralization of IFNalpha/beta mimicked the phenotype of NOS2-/- mice. Thus, IFNalpha/beta and NOS2 are critical regulators of the innate response to L. major.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / pharmacology
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Cytokines / biosynthesis
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Cytokines / immunology
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Cytotoxicity, Immunologic
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Down-Regulation
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Female
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Humans
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Interferon Type I / immunology*
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Interferon-gamma / immunology
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Isoenzymes / biosynthesis
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Isoenzymes / immunology*
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Killer Cells, Natural / immunology
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Leishmania major*
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Leishmaniasis, Cutaneous / immunology*
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Macrophages / enzymology
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Macrophages / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / immunology*
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Rabbits
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Th1 Cells / immunology
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Transforming Growth Factor beta / biosynthesis
Substances
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Antibodies
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Cytokines
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Interferon Type I
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Isoenzymes
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Transforming Growth Factor beta
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Interferon-gamma
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Nitric Oxide Synthase