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The Journal of Immunology, 2007, 179, 5462-5473
Copyright © 2007 by The American Association of Immunologists, Inc.
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Identification of the IL-17 Receptor Related Molecule IL-17RC as the Receptor for IL-17F

Rolf E. Kuestner*, David W. Taft{dagger}, Aaron Haran*, Cameron S. Brandt*, Ty Brender*, Karen Lum*, Brandon Harder{dagger}, Shannon Okada{dagger}, Craig D. Ostrander{ddagger}, James L. Kreindler, Shean J. Aujla, Brian Reardon{ddagger}, Margaret Moore{ddagger}, Pamela Shea{ddagger}, Randall Schreckhise{ddagger}, Thomas R. Bukowski{ddagger}, Scott Presnell§, Patricia Guerra-Lewis{ddagger}, Julia Parrish-Novak*, Jeff L. Ellsworth{dagger}, Stephen Jaspers{dagger}, Katherine E. Lewis{dagger}, Mark Appleby*, Jay K. Kolls, Mark Rixon{ddagger}, James W. West*, Zeren Gao§ and Steven D. Levin1,{dagger}

* Departments of Molecular and Cell Based Discovery, {dagger} Autoimmunity and Inflammation, {ddagger} Protein Biochemistry, and § Bioinformatics, ZymoGenetics Incorporated, Seattle, WA 98102; and Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213

The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.

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 Address correspondence and reprint requests to Dr. Steven D. Levin, Department of Autoimmunity and Inflammation, ZymoGenetics, Incorporated, 1201 Eastlake Avenue East, Seattle, WA 98102. E-mail address: slev{at}zgi.com

2 Abbreviations used in this paper: hIL-17RC, human IL-17RC; hIL-17F, human IL-17F; hIL-17A, human IL-17A; BB, binding buffer; SAEC, small airway epithelium cell; BAL, bronchial alveolar lavage; HBE, human bronchial epithelial cell; BHK, baby hamster kidney cell.




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