Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes.
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-alpha 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-alpha. Based on a cooperation index, 130 and 203 genes were synergistically induced by IL-17A or IL-17F plus TNF-alpha, 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-alpha. IL-17A and IL-17F are both expressed in RA synovium. In the presence of TNF-alpha, they induced a similar expression pattern in RA synoviocytes. Accordingly, IL-17F appears as a target in Th17-mediated diseases such as RA.
Zrioual
Saloua
S
Department of Immunology and Rheumatology and Hospices Civils de Lyon-bioMerieux Mixed Research Unit, Hospital Edouard Herriot, Lyon, France.
Ecochard
René
R
Tournadre
Anne
A
Lenief
Vanina
V
Cazalis
Marie-Angélique
MA
Miossec
Pierre
P
D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C508717:IL17A protein, human; C440021:IL17F protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha