Cutting Edge: Stat6-Dependent Substrate Depletion Regulates Nitric Oxide Production

• Published in: The Journal of immunology (1950) Vol. 166; no. 4; pp. 2173 - 2177
• Main Authors: Rutschman, Robert, Lang, Roland, Hesse, Matthias, Ihle, James N, Wynn, Thomas A, Murray, Peter J
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.02.2001
• Subjects: Animals; Arginase - biosynthesis; Arginine - deficiency; Cells, Cultured; Down-Regulation - immunology; Interleukin-13 - physiology; Interleukin-4 - physiology; Macrophage Activation; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - parasitology; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; STAT6 Transcription Factor; Substrate Specificity - immunology; Toxoplasmosis, Animal - enzymology; Toxoplasmosis, Animal - immunology; Toxoplasmosis, Animal - metabolism; Trans-Activators - deficiency; Trans-Activators - genetics; Trans-Activators - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.4.2173

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.