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IL-13 Receptor 2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung¹

Tao Zheng^2,*, Wei Liu, Sun-Young Oh^*, Zhou Zhu^*, Buqu Hu, Robert J. Homer, Lauren Cohn, Michael J. Grusby and Jack A. Elias

^* Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224; Department of Internal Medicine and Department of Pathology, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06510; and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115

IL-13 is a critical cytokine at sites of Th2 inflammation. In these locations it mediates its effects via a receptor complex, which contains IL-4R and IL-13R1. A third, high-affinity IL-13 receptor, IL-13R2, also exists. Although it was initially felt to be a decoy receptor, this has not been formally demonstrated and the role(s) of this receptor has recently become controversial. To define the role(s) of IL-13R2 in IL-13-induced pulmonary inflammation and remodeling, we compared the effects of lung-targeted transgenic IL-13 in mice with wild-type and null IL-13R2 loci. We also investigated the effect of IL-13R2 deficiency on the OVA-induced inflammatory response. In this study, we show that in the absence of IL-13R2, IL-13-induced pulmonary inflammation, mucus metaplasia, subepithelial fibrosis, and airway remodeling are significantly augmented. These changes were accompanied by increased expression and production of chemokines, proteases, mucin genes, and TGF-β1. Similarly, an enhanced inflammatory response was observed in an OVA-induced phenotype. In contrast, disruption of IL-13R2 had no effect on the tissue effects of lung-targeted transgenic IL-4. Thus, IL-13R2 is a selective and powerful inhibitor of IL-13-induced inflammatory, remodeling, and physiologic responses in the murine lung.

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 National Institutes of Health Grants AI55064 (to T.Z.); HL074095 and HL079349 (to Z.Z.); and HL64242, HL078744, HL56389, and HL081639 (to J.A.E.).

² Address correspondence and reprint requests to Dr. Tao Zheng, Johns Hopkins University, 5501 Hopkins Bayview Circle, 3B.69, Baltimore, MD 21224. E-mail address: tzheng{at}jhmi.edu

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; WT, wild type; rtTA, reverse tetracycline transactivator; Dox, doxycycline; BAL, bronchoalveolar lavage; Tg, transgenic; MMP, matrix metalloproteinase.

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