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Genome-Wide Comparison between IL-17A- and IL-17F-Induced Effects in Human Rheumatoid Arthritis Synoviocytes¹

Saloua Zrioual^*, René Ecochard, Anne Tournadre, Vanina Lenief^*, Marie-Angélique Cazalis^* and Pierre Miossec^2,*

^* Department of Immunology and Rheumatology and Hospices Civils de Lyon-bioMerieux Mixed Research Unit, Hospital Edouard Herriot, Lyon; and Department of Biostatistics, Hospices Civils, Lyon, France

IL-17A is implicated in rheumatoid arthritis (RA) pathogenesis; however, the contribution of IL-17F remains to be clarified. Using microarrays and gene-specific expression assays, we compared the regulatory effects of IL-17A and IL-17F alone or in combination with TNF- on RA synoviocytes. IL-17A and IL-17F expression was studied in osteoarthritis and RA synovium by immunohistochemistry. The comparison between the IL-17A and IL-17F stimulatory effect on RA synoviocytes was assessed at the protein level by ELISA and at the mRNA level by microarrays and real-time RT-PCR. TNFRII expression was studied by real-time RT-PCR and immunofluorescence, and neutralizing Ab was used to analyze its contribution to CCL20 secretion. IL-17A and IL-17F were detected in plasma cell-like cells from RA but not osteoarthritis synovium. In microarrays, IL-17A and IL-17F alone had similar regulatory effects, IL-17F being quantitatively less active. Both cytokines induced a similar expression pattern in the presence of TNF-. Based on a cooperation index, 130 and 203 genes were synergistically induced by IL-17A or IL-17F plus TNF-, respectively. Among these, the new target genes CXCR4, LPL, and IL-32 were validated by real-time RT-PCR. IL-17A and IL-17F up-regulated TNFRII expression, but had no effects on TNFRI, IL-17RA or IL-17RC. TNFRII blockade inhibited the synergistic induction of CCL20 by IL-17A or IL-17F and TNF-. IL-17A and IL-17F are both expressed in RA synovium. In the presence of TNF-, they induced a similar expression pattern in RA synoviocytes. Accordingly, IL-17F appears as a target in Th17-mediated diseases such as RA.

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 has been supported in part by grants from the Hospices Civils de Lyon and the Region Rhône-Alpes. S.Z. is supported by a scholarship 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, OA, osteoarthritis; LPL, lipoprotein lipase; ARE, AU-rich element.

⁴ The online version of this article contains supplemental material.