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

• Published in: The Journal of immunology (1950) 2008-09, Vol.181 (6), p.4299-4310
• Main Authors: Rickel, Erika A, Siegel, Lori A, Yoon, Bo-Rin Park, Rottman, James B, Kugler, David G, Swart, David A, Anders, Penny M, Tocker, Joel E, Comeau, Michael R, Budelsky, Alison L
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Humans; Interleukin-17 - metabolism; Interleukin-17 - physiology; Interleukins - deficiency; Interleukins - genetics; Interleukins - metabolism; Interleukins - physiology; Ligands; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Rats; Rats, Inbred Lew; Receptors, Interleukin - deficiency; Receptors, Interleukin - genetics; Receptors, Interleukin - physiology; Receptors, Interleukin-17 - deficiency; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.6.4299

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.