The Journal of Experimental Medicine
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Published 17 March 2003. doi:10.1084/jem.20020903
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© Rockefeller University Press, 0022-1007/2003/3/687 $5.00
The Journal of Experimental Medicine, Volume 197, Number 6, 687-701

Regulation and Function of the Interleukin 13 Receptor {alpha} 2 During a T Helper Cell Type 2–dominant Immune Response

Monica G. Chiaramonte1, Margaret Mentink-Kane1, Bruce A. Jacobson2, Allen W. Cheever3, Matthew J. Whitters2, Mary E.P. Goad2, Anthony Wong2, Mary Collins2, Debra D. Donaldson2, Michael J. Grusby4 and Thomas A. Wynn1

1 Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892
2 Wyeth-Genetics Institute, Cambridge, MA 01810
3 Biomedical Research Institute, Rockville, MD 20852
4 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115

Address correspondence to Thomas A. Wynn, Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50, Room 6154, MSC 8003, Bethesda, MD 20892. Phone: 301-496-4758; Fax: 301-480-5025; E-mail: twynn{at}niaid.nih.gov

Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of T helper cell (Th)2-dominant immune responses, exhibiting a diverse array of functional activities including regulation of airway hyperreactivity, resistance to nematode parasites, and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R){alpha}2 is a critical down-regulatory factor of IL-13–mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni. IL-13R{alpha}2 expression was induced after the onset of the fibrotic response, IL-10, IL-13, and Stat6 dependent, and inhibited by the Th1-inducing adjuvant IL-12. Strikingly, schistosome-infected C57BL/6 and BALB/c IL-13R{alpha}2–deficient mice showed a marked exacerbation in hepatic fibrosis, despite displaying no change in granuloma size, tissue eosinophilia, or mastocytosis. Fibrosis increased despite the fact that IL-13 levels decreased significantly in the liver and serum. Importantly, pathology was prevented when IL-13R{alpha}2–deficient mice were treated with a soluble IL-13R{alpha}2-Fc construct, formally demonstrating that their exacerbated fibrotic response was due to heightened IL-13 activity. Together, these studies illustrate the central role played by the IL-13R{alpha}2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response.

Key Words: fibrosis • inflammation • liver • granuloma • mouse


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