| Abstract
| - Background. Patients with rheumatoid arthritis (RA) have a systemic Th1 defect associated with inflammation. Objective. To examine the hypothesis that interleukin 17 (IL-17) contributes to this defect. Methods. IL-17 effects on Th1 markers were examined on T-bet and interferon γ (IFNγ) expression in peripheral blood mononuclear cells (PBMCs) from patients with RA or healthy controls (HC). Receptor specificities were determined by analysis of the Th1-specific IL-12 receptor β2 (IL-12Rβ2), Th17-specific IL-23R and the common IL-12Rβ1 chain expression. Effects of IL-17 or IFNγ on IL-6, IL-1, IL-8, matrix metalloproteinase-8 (MMP-8) were measured by real-time RT-PCR in RA synovial cells. Results. RA PBMCs were less responsive to IL-12-induced IFNγ than HC PBMCs. IL-12 hyporesponsiveness was increased by IL-17 treatment associated with a selective reduction in IL-12Rβ2, but not IL-23R, IL-12Rβ1 or T-bet, which was reversed with IL-17R inhibition. IL-17 inhibited IL-12Rβ2 expression in developing Th1 cells. In RA synovial cells, IL-17 induced IL-6, IL-1, IL-8 and MMP-8, whereas IFNγ had minimal or inhibitory effects. Conclusion. In RA, IL-12 hyporesponsiveness is associated with IL-17R-mediated downregulation of IL-12Rβ2 expression. IL-17 may reinforce Th17 lineage commitment and proinflammatory and destructive effects through Th1 inhibition and positive feedback effects in RA synovial cells. Anti-inflammatory effects of IL-17/IL-17R antagonism may include the restoration of protective Th1 responses.
|
