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Identification of Functional Roles for Both IL-17RB and IL-17RA in Mediating IL-25-Induced Activities

Erika A. Rickel^*, Lori A. Siegel^*, Bo-Rin Park Yoon^*, James B. Rottman, David G. Kugler^*, David A. Swart^*, Penny M. Anders^*, Joel E. Tocker^*, Michael R. Comeau^* and Alison L. Budelsky^1,*

^* Department of Inflammation Research, Amgen, Seattle, WA 98119; and Department of Pathology, Amgen, Cambridge, MA 02139

IL-25 (IL-17E) is a unique IL-17 family ligand that promotes Th2-skewed inflammatory responses. Intranasal administration of IL-25 into naive mice induces pulmonary inflammation similar to that seen in patients with allergic asthma, including increases in bronchoalveolar lavage fluid eosinophils, bronchoalveolar lavage fluid IL-5 and IL-13 concentrations, goblet cell hyperplasia, and increased airway hyperresponsiveness. IL-25 has been reported to bind and signal through IL-17RB (IL-17BR, IL-17Rh1). It has been demonstrated recently that IL-17A signals through a heteromeric receptor composed of IL-17RA and IL-17RC. We sought to determine whether other IL-17 family ligands also utilize heteromeric receptor complexes. The required receptor subunits for IL-25 biological activities were investigated in vitro and in vivo using a combination of knockout (KO) mice and antagonistic Abs. Unlike wild-type mice, cultured splenocytes from either IL-17RB KO or IL-17RA KO mice did not produce IL-5 or IL-13 in response to IL-25 stimulation, and both IL-17RB KO and IL-17RA KO mice did not respond to intranasal administration of IL-25. Furthermore, treatment with antagonistic mAbs to either IL-17RB or IL-17RA completely blocked IL-25-induced pulmonary inflammation and airway hyperresponsiveness in naive BALB/c mice, similar to the effects of an antagonistic Ab to IL-25. Finally, a blocking Ab to human IL-17RA prevented IL-25 activity in a primary human cell-based assay. These data demonstrate for the first time that IL-25-mediated activities require both IL-17RB and IL-17RA and provide another example of an IL-17 family ligand that utilizes a heteromeric receptor complex.

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. Alison Budelsky, Amgen, 1201 Amgen Court West, Seattle, WA 98119. E-mail address: alisonb{at}amgen.com

² Abbreviations used in this paper: KO, knockout; WT, wild type; BALF, bronchoalveolar lavage fluid; BAL, bronchoalveolar lavage; AHR, airway hyperresponsiveness; MCh, methacholine; PAS, periodic acid-Schiff; TSLP, thymic stromal lymphopoietin; i.n. = intranasal; PENH, enhanced pause; TRAF6, TNFR-associated factor 6.