title: Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production.
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.
authors.affiliation: Department of Infectious Diseases, Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rutschman
authors.forename: R
authors.initials: R
authors.lastname: Lang
authors.forename: M
authors.initials: M
authors.lastname: Hesse
authors.forename: J N
authors.initials: JN
authors.lastname: Ihle
authors.forename: T A
authors.initials: TA
authors.lastname: Wynn
authors.forename: P J
authors.initials: PJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D001120:Arginine / Q000172:deficiency; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D050800:STAT6 Transcription Factor; D013379:Substrate Specificity / Q000276:immunology; D014124:Toxoplasmosis, Animal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase