title: Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.
abstract: 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.
authors.affiliation: Department of Inflammation Research, Amgen, Seattle, WA 98119, USA.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Rickel
authors.forename: Lori A
authors.initials: LA
authors.lastname: Siegel
authors.forename: Bo-Rin Park
authors.initials: BR
authors.lastname: Yoon
authors.forename: James B
authors.initials: JB
authors.lastname: Rottman
authors.forename: David G
authors.initials: DG
authors.lastname: Kugler
authors.forename: David A
authors.initials: DA
authors.lastname: Swart
authors.forename: Penny M
authors.initials: PM
authors.lastname: Anders
authors.forename: Joel E
authors.initials: JE
authors.lastname: Tocker
authors.forename: Michael R
authors.initials: MR
authors.lastname: Comeau
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky