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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. Carreno^5,*

^* Department of Inflammation and Biological Technologies, Wyeth Research, Cambridge, MA, 02140

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 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 exploited to differentially affect the activity of these cytokines.

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. Jill F. Wright, Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140. E-mail address: jwright{at}wyeth.com

² F.B. and B.L. contributed equally to this work.

³ Current address: Acceleron Pharma, 24 Emily Street, Cambridge, MA 02139.

⁴ Current address: Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064.

⁵ Current address: Washington University School of Medicine, Division of Oncology, 660 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110.

⁶ Abbreviations used in this paper: siRNA, small interfering RNA; GRO-, growth-related oncogene-alpha.

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