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IL-17RA/IL-17RC Receptor Complex Cytokine Signals Through the The The Human IL-17F/IL-17A Heterodimeric Cytokine Signals through the IL-17RA/IL-17RC Receptor Complex This information is current as Jill F. Wright, Frann Bennett, Bilian Li, Jonathan Brooks, of October 1, 2021. Deborah P. Luxenberg, Matthew J. Whitters, Kathleen N. Tomkinson, Lori J. Fitz, Neil M. Wolfman, Mary Collins, Kyri Dunussi-Joannopoulos, Moitreyee Chatterjee-Kishore and Beatriz M. Carreno J Immunol 2008; 181:2799-2805; ; doi: 10.4049/jimmunol.181.4.2799 Downloaded from http://www.jimmunol.org/content/181/4/2799 References This article cites 32 articles, 14 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/181/4/2799.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Human IL-17F/IL-17A Heterodimeric Cytokine Signals through the IL-17RA/IL-17RC Receptor Complex Jill F. Wright,1* Frann Bennett,2* Bilian Li,2† Jonathan Brooks,* Deborah P. Luxenberg,* Matthew J. Whitters,* Kathleen N. Tomkinson,3* Lori J. Fitz,* Neil M. Wolfman,* Mary Collins,* Kyri Dunussi-Joannopoulos,* Moitreyee Chatterjee-Kishore,4† and Beatriz M. Carreno5* IL-17A and IL-17F, produced by the Th17 CD4؉ T cell lineage, have been linked to a variety of inflammatory and autoimmune conditions. We recently reported that activated human CD4؉ T cells produce not only IL-17A and IL-17F homodimers but also an IL-17F/IL-17A heterodimeric cytokine. All three cytokines can induce chemokine secretion from bronchial epithelial cells, albeit with different potencies. In this study, we used small interfering RNA and Abs to IL-17RA and IL-17RC to demonstrate that heterodimeric IL-17F/IL-17A cytokine activity is dependent on the IL-17RA/IL-17RC receptor complex. Interestingly, surface Downloaded from plasmon resonance studies indicate that the three cytokines bind to IL-17RC with comparable affinities, whereas they bind to IL-17RA with different affinities. Thus, we evaluated the effect of the soluble receptors on cytokine activity and we find that soluble receptors exhibit preferential cytokine blockade. IL-17A activity is inhibited by IL-17RA, IL-17F is inhibited by IL-17RC, and a combination of soluble IL-17RA/IL-17RC receptors is required for inhibition of the IL-17F/IL-17A activity. Altogether, these results indicate that human IL-17F/IL-17A cytokine can bind and signal through the same receptor complex as human IL-17F and IL-17A. However, the distinct affinities of the receptor components for IL-17A, IL-17F, and IL-17F/IL-17A heterodimer can be http://www.jimmunol.org/ exploited to differentially affect the activity of these cytokines. The Journal of Immunology, 2008, 181: 2799–2805. nterleukin 17A (IL-17A) is the founding member of the likely that IL-17A and IL-17F adopt a similar structure. Recently, proinflammatory IL-17 cytokine family. This cytokine family we have shown that activated human CD4ϩ T cells not only ex- I consists of six members (A–F), with IL-17A and IL-17F press IL-17A and IL-17F homodimers, but also an IL-17F/IL-17A sharing the closest amino acid sequence identity of ϳ50%. IL-17A heterodimer, and that the conserved cysteines used in the knot and IL-17F are homodimeric cytokines produced by the Th17 T formation of IL-17A and IL-17F homodimers are the cysteines cell lineage and share similar biological activities, including in- involved in the disulfide linkage of the IL-17F/IL-17A heterodimer by guest on October 1, 2021 duction of cytokines and chemokines involved in inflammatory (20). The murine IL-17F/IL-17A heterodimer has also been shown responses (1–7). IL-17A and IL-17F have been implicated in a to be expressed by differentiated Th17 cells (21, 22). variety of autoimmune diseases, such as rheumatoid arthritis, mul- The IL-17 receptor family consists of five members: RA, RB, tiple sclerosis, inflammatory bowel disease, asthma, and psoriasis RC, RD, and RE. IL-17A has been shown to bind IL-17RA (also (5, 6, 8–16). referred to as IL-17R) with high affinity, and IL-17RA is required The crystal structure of IL-17F has been reported (17) and for the biological activity of IL-17A (17, 23, 24). Binding of IL- shows that IL-17F forms a disulfide-linked dimer that contains a 17F to IL-17RA was not detected by surface plasmon resonance; cysteine knot motif similar to that reported for members of the however, weak binding of IL-17F to cells expressing IL-17RA was nerve growth factor and TGF-␤ superfamilies (18, 19). Given the detected, suggesting that both IL-17A and IL-17F utilize IL-17RA high degree of amino acid homology between IL-17A and IL-17F as part of their receptor complex (17). The IL-17RA receptor is a and the conservation of the four cysteines that form the knot, it is preformed multimeric complex and is thought to undergo a con- formational change upon binding to IL-17A or IL-17F (25). *Department of Inflammation and †Biological Technologies, Wyeth Research, Cam- It has been shown that IL-17A cannot bind to T cells, B cells, bridge, MA, 02140 and myeloid cells that are deficient in IL-17RA (24). Toy et al. Received for publication August 23, 2007. Accepted for publication June 2, 2008. showed that human IL-17A or IL-17F could not elicit a response Ϫ/Ϫ The costs of publication of this article were defrayed in part by the payment of page on mouse IL-17RA cells and the activity could only be re- charges. This article must therefore be hereby marked advertisement in accordance gained by the cotransfection of human IL-17RA and IL-17RC, with 18 U.S.C. Section 1734 solely to indicate this fact. demonstrating that both IL-17RA and IL-17RC are necessary for 1 Address correspondence and reprint requests to Dr. Jill F. Wright, Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140. the biological activity of IL-17A and IL-17F (26). More recently, E-mail address: [email protected] it has been shown that a soluble form of IL-17RC could neutralize 2 F.B. and B.L. contributed equally to this work. the activity of IL-17A and IL-17F on human bronchial epithelial 3 Current address: Acceleron Pharma, 24 Emily Street, Cambridge, MA 02139. cells stimulated with IL-17 cytokine plus TNF-␣ (27). 4 Current address: Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL In this report, we investigate the roles of IL-17RA and IL-17RC 60064. receptors in mediating the biological activity of the IL-17F/IL-17A 5 Current address: Washington University School of Medicine, Division of Oncology, heterodimer. We find that the heterodimer, along with IL-17A and 660 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110. IL-17F homodimers, requires IL-17RA and IL-17RC receptors for Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 signaling. Additionally, our results strongly suggest that different www.jimmunol.org 2800 IL-17F/IL-17A SIGNALS THROUGH IL-17RA/IL-17RC COMPLEX Table I. siRNAs used for human IL-17RA and IL-17RC knockdown siRNA Cat. No. Sequence Hs_IL17R_1_HP S100104979 CAG CGG TCT GGT TAT CGT CTA Hs_IL17R_2_HP S100104986 CGG CAC CTA CGT AGT CTG CTA Hs_IL17R_3_HP S100104993 CAG GAA GGT CTG GAT CAT CTA Hs_IL17R_4_HP S100105000 CAG GTT TGA GTT TCT GTC CAA Hs_IL17RC_1_HP S100144165 ACC GCA GAT CAT TAC CTT GAA Hs_IL17RC_2_HP S100144172 CAG GTA CGA GAA GGA ACT CAA Hs_IL17RC_3_HP S100144179 CGG GAC TTA AAT AAA GGC AGA Hs_IL17RC_4_HP S100144186 CCG CGC GGC TCT GCT CCT CTA biological activities among homodimers and heterodimer of IL- ng/ml) was added to plates and incubated for 3 h, followed by serial di- 17A and IL-17F cytokines may be attributed to affinity differences lutions of biotinylated IL-17A, IL-17F, and IL-17F/IL-17A for2hatroom among these cytokines for IL-17RA and IL-17RC receptors. temperature. ELISA was developed with poly-HRP strepavidin (Pierce Biotechnology) and tetramethylbenzidine substrate (Kirkegaard & Perry Laboratories). Materials and Methods Reagents siRNA Human IL-17F, IL-17A, and IL-17F/IL-17A were purified as previously Twenty-four hours before transfection, BJ cells were seeded at 104 cells/ Downloaded from described (20) and used in all experiments except small interfering RNA well in 96-well plates. Cells were transfected with siRNA (20 nM) using (siRNA)6 experiments, where IL-17A from R&D Systems was used. IL- DharmaFECT 1 transfection reagent (Dharmacon) according to the man- 17F, IL-17A, and IL-17F/IL-17A were biotinylated according to the man- ufacturer’s instructions. Each transfection contained one of eight siRNAs ufacturer’s protocol using FluoReporter Minibiotin-XX protein labeling kit listed in Table I. siRNAs were obtained from Qiagen. At 24 h, transfection (Molecular Probes).
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