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IL-17RA and IL-17RC Receptors Are Essential for IL-17A-Induced ELR⁺ CXC Chemokine Expression in Synoviocytes and Are Overexpressed in Rheumatoid Blood¹

Department of Immunology and Rheumatology, Mixed Unit Civil Hospital of Lyon-Biomerieux, Edouard Herriot Hospital, Lyon, France

IL-17A is a cytokine secreted by the newly described Th17 cells implicated in rheumatoid arthritis (RA). Less is known about its receptors in synoviocytes. IL-17RA and IL-17RC were found to be overexpressed in RA peripheral whole blood and their expression was detected locally in RA synovium. In vitro, IL-17A synergized with TNF- to induce IL-6, IL-8, CCL-20, and matrix metalloproteinase-3. Using microarrays, a specific up-regulation of Glu-Leu-Arg⁺ CXC chemokines was observed in IL-17A-treated synoviocytes. Using both posttranslational inhibitions by silencing interfering RNA and extracellular blockade by specific inhibitors, we showed that both IL-17RA and IL-17RC are implicated in IL-17A-induced IL-6 secretion, whereas in the presence of TNF-, the inhibition of both receptors was needed to down-regulate IL-17A-induced IL-6 and CCL-20 secretion. Thus, IL-17A-induced IL-6, IL-8, and CCL20 secretion was dependent on both IL-17RA and IL-17RC, which are overexpressed in RA patients. IL-17A-induced pathogenic effects may be modulated by IL-17RA and/or IL-17RC antagonism.

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 This work was supported in part by grants from the Hospices Civils of Lyon and the Region Rhône-Alpes. S.Z. was supported by a scholarship from the Region Rhône-Alpes. M.-L.T. and Y.Z. were supported by a fellowship from the Region Rhône-Alpes.

² Address correspondence and reprint requests to Prof. Pierre Miossec, Clinical Immunology Unit, Department of Immunology and Rheumatology, Hospital Edouard Herriot, 69437 Lyon Cedex 03, France. E-mail address: pierre.miossec{at}univ-lyon1.fr

³ Abbreviations used in this paper: RA, rheumatoid arthritis; siRNA, silencing interfering RNA; OA, osteoarthritis; HV, healthy volunteer; DAS, disease activity score; MMP, matrix metalloproteinase; HPRT1, hypoxanthine phosphoribosyltransferase 1; AU, arbitrary unit; ELR, Glu-Leu-Arg; PPIB, peptidylpropyl isomerase B.