The Human IL-17F/IL-17A Heterodimeric Cytokine Signals through the IL-17RA/IL-17RC Receptor Complex

• Published in: The Journal of immunology (1950) Vol. 181; no. 4; pp. 2799 - 2805
• Main Authors: Wright, Jill F, Bennett, Frann, Li, Bilian, Brooks, Jonathan, Luxenberg, Deborah P, Whitters, Matthew J, Tomkinson, Kathleen N, Fitz, Lori J, Wolfman, Neil M, Collins, Mary, Dunussi-Joannopoulos, Kyri, Chatterjee-Kishore, Moitreyee, Carreno, Beatriz M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.08.2008
• Subjects: Cell Line; Dimerization; Dose-Response Relationship, Immunologic; Humans; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - chemistry; Interleukin-17 - metabolism; Interleukin-17 - physiology; Protein Binding - immunology; Receptors, Interleukin - metabolism; Receptors, Interleukin - physiology; Receptors, Interleukin-17 - metabolism; Receptors, Interleukin-17 - physiology; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.4.2799

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.