Abstract
Interleukin-12 (IL-12) and type 2 NO synthase (NOS2) are crucial for defense against bacterial and parasitic pathogens, but their relationship in innate immunity is unknown. In the absence of NOS2 activity, IL-12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer (NK) cells for cytotoxicity or interferon-gamma (IFN-gamma) release, and failed to activate Tyk2 kinase and to tyrosine phosphorylate Stat4 (the central signal transducer of IL-12) in NK cells. Activation of Tyk2 in NK cells by IFN-alpha/beta also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cells, Cultured
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Cyclic GMP / metabolism
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Cytotoxicity, Immunologic
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DNA-Binding Proteins / metabolism
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Immunity, Innate
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interferons / pharmacology
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Interleukin-12 / pharmacology
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Interleukin-12 / physiology*
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Janus Kinase 2
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Leishmania major*
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Leishmaniasis, Cutaneous / immunology*
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Leishmaniasis, Cutaneous / metabolism
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Lysine / analogs & derivatives
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Lysine / pharmacology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism*
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Nitric Oxide Synthase Type II
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins*
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STAT4 Transcription Factor
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Signal Transduction*
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TYK2 Kinase
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Trans-Activators / metabolism
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Up-Regulation
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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N(6)-(1-iminoethyl)lysine
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Proteins
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Proto-Oncogene Proteins
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STAT4 Transcription Factor
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Stat4 protein, mouse
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Trans-Activators
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Interleukin-12
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Nitric Oxide
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Interferon-gamma
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Interferons
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Protein-Tyrosine Kinases
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Jak2 protein, mouse
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Janus Kinase 2
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TYK2 Kinase
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Tyk2 protein, mouse
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Cyclic GMP
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Lysine