Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production

The cytokines IL-4 and IL-13 inhibit the production of NO from activated ma crophages through an unresolved molecular mechanism. We show here that IL-4 and IL-13 regulate NO production through depletion of arginine, the substr ate of inducible NO synthase (iNOS). Inhibition of NO production from murin e macrophages stimulated with LPS and IFN-gamma by IL-4 or IL-13 was depend ent 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 bu t up-regulated arginase I (the liver isoform of arginase) in a Stat6-depend ent manner. Addition of exogenous arginine completely restored NO productio n in IL-4-treated macrophages, Furthermore, impaired killing of the intrace llular pathogen Toxoplasma gondii in IL-4-treated macrophages was overcome by supplementing L-arginine. The simple system of regulated substrate compe tition between arginase and iNOS has implications for understanding the phy siological regulation of NO production.