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

R Rutschman, R Lang, M Hesse, JN Ihle… - The Journal of …, 2001 - journals.aai.org
R Rutschman, R Lang, M Hesse, JN Ihle, TA Wynn, PJ Murray
The Journal of Immunology, 2001journals.aai.org
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-γ 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 …
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-γ 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.
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