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CUTTING EDGE |
Departments of
*
Infectious Diseases and
Biochemistry and Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis, TN 38105; and
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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-
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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