Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.
The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.
Kuestner
Rolf E
RE
Department of Molecular and Cell Based Discovery, ZymoGenetics Incroporated, Seattle, WA 98102, USA.
Taft
David W
DW
Haran
Aaron
A
Brandt
Cameron S
CS
Brender
Ty
T
Lum
Karen
K
Harder
Brandon
B
Okada
Shannon
S
Ostrander
Craig D
CD
Kreindler
James L
JL
Aujla
Shean J
SJ
Reardon
Brian
B
Moore
Margaret
M
Shea
Pamela
P
Schreckhise
Randall
R
Bukowski
Thomas R
TR
Presnell
Scott
S
Guerra-Lewis
Patricia
P
Parrish-Novak
Julia
J
Ellsworth
Jeff L
JL
Jaspers
Stephen
S
Lewis
Katherine E
KE
Appleby
Mark
M
Kolls
Jay K
JK
Rixon
Mark
M
West
James W
JW
Gao
Zeren
Z
Levin
Steven D
SD
D017398:Alternative Splicing / Q000276:immunology; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000627:therapeutic use; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D013045:Species Specificity; D014162:Transfection
D018836:Inflammation Mediators; D020381:Interleukin-17; D053722:Receptors, Interleukin-17