IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood.
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-alpha 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-alpha, 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.
Zrioual
Saloua
S
Department of Immunology and Rheumatology, Mixed Unit Civil Hospital of Lyon-Biomerieux, Lyon, France.
Toh
Myew-Ling
ML
Tournadre
Anne
A
Zhou
Yuan
Y
Cazalis
Marie-Angélique
MA
Pachot
Alexandre
A
Miossec
Vincent
V
Miossec
Pierre
P
D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000276:immunology*; D016022:Case-Control Studies; D054418:Chemokine CCL20 / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D013583:Synovial Membrane / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054418:Chemokine CCL20; D019743:Chemokines, CXC; C508717:IL17A protein, human; C109985:IL17RA protein, human; C448419:IL17RC protein, human; D020381:Interleukin-17; D015850:Interleukin-6; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D014409:Tumor Necrosis Factor-alpha