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* Division of Molecular Biosciences and
Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, Australia;
Division of Allergy and Immunology, Department of Pediatrics, Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229;
Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth, Western Australia; and
¶ Asthma, Allergy, and Inflammation Research Center, School of Biomedical Sciences, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia
Increased arginase I activity is associated with allergic disorders such as asthma. How arginase I contributes to and is regulated by allergic inflammatory processes remains unknown. CD4+ Th2 lymphocytes (Th2 cells) and IL-13 are two crucial immune regulators that use STAT6-dependent pathways to induce allergic airways inflammation and enhanced airways responsiveness to spasmogens (airways hyperresponsiveness (AHR)). This pathway is also used to activate arginase I in isolated cells and in hepatic infection with helminths. In the present study, we show that arginase I expression is also regulated in the lung in a STAT6-dependent manner by Th2-induced allergic inflammation or by IL-13 alone. IL-13-induced expression of arginase I correlated directly with increased synthesis of urea and with reduced synthesis of NO. Expression of arginase I, but not eosinophilia or mucus hypersecretion, temporally correlated with the development, persistence, and resolution of IL-13-induced AHR. Pharmacological supplementation with L-arginine or with NO donors amplified or attenuated IL-13-induced AHR, respectively. Moreover, inducing loss of function of arginase I specifically in the lung by using RNA interference abrogated the development of IL-13-induced AHR. These data suggest an important role for metabolism of L-arginine by arginase I in the modulation of IL-13-induced AHR and identify a potential pathway distal to cytokine receptor interactions for the control of IL-13-mediated bronchoconstriction in asthma.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Health Medical Research Council (NHMRC) (Australia) Program Grant 224207, a NHMRC P.C. Doherty Postdoctoral Fellowship (to S.M. and D.C.W.), an Australian International Postgraduate Research Award (to M.Y.), a University of Newcastle Postdoctoral Fellowship Scheme (to M.Y.), a Clive and Vera Ramaciotti Foundation Establishment Grant (to M.Y.), National Institutes of Health Grant R01 AI1053479 (to M.E.R.), the Human Frontier Science Program (to M.E.R. and P.S.F.), and the Commonwealths Cooperative Research Center for Asthma and Airways (to M.Y. and P.S.F.).
2 Address correspondence and reprint requests to Dr. Paul S. Foster, Asthma, Allergy, and Inflammation Research Center, David Maddison Building, Royal Newcastle Hospital, School of Biomedical Sciences, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Corner of King and Watt Streets, Callaghan, New South Wales, 2300, Australia. E-mail address: Paul.Foster{at}newcastle.edu.au
3 Abbreviations used in this paper: BALF, bronchoalveolar lavage fluid; iNOS, inducible NO synthase; AHR, airways hyperresponsiveness; RNAi, RNA interference; WT, wild type; DETA, diethylenetriamine; RNI, reactive nitrogen intermediate; shRNA, short hairpin RNA; PDM, peritoneal-derived macrophage; Penh, enhanced pause.
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