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

Abstract

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-α 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-α, 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.

Transcription Factors GATA-3 and RORγt Are Important for Determining the Phenotype of Allergic Airway Inflammation in a Murine Model of Asthma

“…MIP-2 is a mouse homolog of human IL-8 (CXCL8), and CXCL8 expression was shown to be elevated and correlated with IL-17A levels and neutrophil counts in the sputum of asthmatic patients (21), indicating the involvement of CXC chemokines in the pathogenesis of neutrophilic airway inflammation in asthma. Previous studies suggested that IL-17 induces CXCL8 secretion from synoviocytes (26), as well as enhances IL-1b-induced CXC8 secretion in lung microvascular endothelial cells (27). Therefore, the upregulation of CXC chemokines in RORgt-tg mice may occur in a Th17 cell-dependent manner.…”

IL-17RC Is Required for IL-17A– and IL-17F–Dependent Signaling and the Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…Furthermore, in human synoviocytes, both IL-17RA and IL-17RC are required for IL-17A-induced chemokine expression (55). The necessity of IL-17RC for the functions of IL-17A and IL-17F is still under debate because of two observations.…”

IL-17A stimulates granulocyte colony-stimulating factor production via ERK1/2 but not p38 or JNK in human renal proximal tubular epithelial cells

“…Therefore, cells with high IL-17RC expression could be highly responsive to IL-17F, whereas those with low IL-17RC expression and high IL-17RA expression might respond better to IL-17A (5). In contrast, a number of studies have suggested that binding to the IL-17RC receptor might not be essential for the activity of IL-17A and IL-17F (11,31,35). Indeed, we found that secreted G-CSF protein was not detected following IL-17F stimulation of HRPTEC culture that significantly expressed IL-17RC on the cell surface, whereas significant G-CSF production was detected in IL-17F-stimulated primary human cortical epithelial cells that do not express IL-17RC.…”