Cutting Edge: Stat6-Dependent Substrate Depletion Regulates Nitric Oxide Production
TLDR
It is shown that IL-4 and IL-13 regulate NO production through depletion of arginine, the substrate of inducible NO synthase (iNOS), which has implications for understanding the physiological regulation of NO 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.read more
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References
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Journal ArticleDOI
Arginine metabolism : nitric oxide and beyond
Guoyao Wu,Sidney M. Morris +1 more
TL;DR: Physiological roles and relationships between the pathways of arginine synthesis and catabolism in vivo are complex and difficult to analyse, owing to compartmentalized expression of various enzymes at both organ and subcellular levels.
Journal ArticleDOI
Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase.
TL;DR: Reporter constructs containing truncated promoter regions revealed that activation of NF-kappa B/Rel is critical in the induction of iNOS by LPS, however, additional, newly synthesized proteins contribute to the NF- kappa Bd-dependent transcription factor complex on the iN OS promoter in LPS-treated mouse macrophages.
Journal ArticleDOI
Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells
Dennis J. Stuehr,Carl Nathan +1 more
TL;DR: M phi-generated NO.
Journal ArticleDOI
Stat6 Is Required for Mediating Responses to IL-4 and for the Development of Th2 Cells
TL;DR: It is demonstrated that, despite the existence of multiple signaling pathways activated by IL-4, Stat6 is essential for mediating responses toIL-4 lymphocytes.
Journal ArticleDOI
Essential role of Stat6 in IL-4 signalling
Kiyoshi Takeda,Takashi Tanaka,Wei Shi,Makoto Matsumoto,Masashi Minami,Shin-ichiro Kashiwamura,Kenji Nakanishi,Nobuaki Yoshida,Tadamitsu Kishimoto,Shizuo Akira +9 more
TL;DR: It is concluded that Stat6 plays a central role in exerting IL-4-mediated biological responses, and production of Th2 cytokines from T cells as well as IgE and IgGl responses after nematode infection were profoundly reduced.