The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex.
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.
Wright
Jill F
JF
Department of Inflammation, Wyeth Research, Cambridge, MA 02140, USA. jwright@wyeth.com
Bennett
Frann
F
Li
Bilian
B
Brooks
Jonathan
J
Luxenberg
Deborah P
DP
Whitters
Matthew J
MJ
Tomkinson
Kathleen N
KN
Fitz
Lori J
LJ
Wolfman
Neil M
NM
Collins
Mary
M
Dunussi-Joannopoulos
Kyri
K
Chatterjee-Kishore
Moitreyee
M
Carreno
Beatriz M
BM
D002460:Cell Line; D019281:Dimerization; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000276:immunology; D018123:Receptors, Interleukin / Q000378:metabolism / Q000502:physiology*; D053722:Receptors, Interleukin-17 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
C109985:IL17RA protein, human; C448419:IL17RC protein, human; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17