Abstract
IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that plays critical roles in the pathogenesis of multiple autoimmune diseases. IL-17RA is a ubiquitously expressed receptor that is essential for IL-17 biologic activity. Despite widespread receptor expression, the activity of IL-17 is most classically defined by its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators by stromal cells. The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary component whose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family. Thus, the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, suggesting a new paradigm for understanding the interactions between the expanded family of IL-17 ligands and their receptors.
Highlights
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IL-17RA engagement on fibroblasts leads to the induction of inflammatory chemokine and cytokine expression [22,23,24]
We sought to develop a system in which IL-17RA variants could be introduced into IL-17RAϪ/Ϫ fibroblasts and assayed for their ability to induce known IL-17 target genes
Summary
Dean Toy,* David Kugler,* Martin Wolfson,† Tim Vanden Bos,† Jesse Gurgel,‡ Jonathan Derry,§ Joel Tocker,* and Jacques Peschon1* The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary component whose activity is species specific. Leukocytes from mice lacking IL-17RA fail to bind IL-17, and Abs against IL-17RA inhibit the activity of IL-17 on human epithelial cells, indicating that IL-17RA is critical for IL-17 function [3, 4].
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