Abstract
The cytokines IL-4 and IL-13 inhibit the production of NO from activated macrophages through an unresolved molecular mechanism. We show here that IL-4 and IL-13 regulate NO production through depletion of arginine, the substrate of inducible NO synthase (iNOS). Inhibition of NO production from murine macrophages stimulated with LPS and IFN-gamma by IL-4 or IL-13 was dependent on Stat6, cell density in the cultures, and pretreatment for at least 6 h. IL-4/IL-13 did not interfere with the expression or activity of iNOS but up-regulated arginase I (the liver isoform of arginase) in a Stat6-dependent manner. Addition of exogenous arginine completely restored NO production in IL-4-treated macrophages. Furthermore, impaired killing of the intracellular pathogen Toxoplasma gondii in IL-4-treated macrophages was overcome by supplementing L-arginine. The simple system of regulated substrate competition between arginase and iNOS has implications for understanding the physiological regulation of NO production.
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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Arginase / biosynthesis
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Arginine / deficiency
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Cells, Cultured
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Down-Regulation / immunology
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Interleukin-13 / physiology
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Interleukin-4 / physiology
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Macrophage Activation
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Macrophages, Peritoneal / enzymology
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Macrophages, Peritoneal / parasitology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide / biosynthesis*
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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STAT6 Transcription Factor
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Substrate Specificity / immunology
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Toxoplasmosis, Animal / enzymology
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Toxoplasmosis, Animal / immunology
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Toxoplasmosis, Animal / metabolism
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology*
Substances
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Interleukin-13
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Trans-Activators
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Interleukin-4
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Nitric Oxide
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Arginine
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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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Arginase