THU0036 Synovial Fibroblasts Directly Induce Th17 Pathogenicity VIA the Cyclooxygenase/Prostaglandin-E2 Pathway, Independent of IL-23. (23rd January 2014)

• Record Type: Journal Article
• Authors: Paulissen, S.; van Hamburg, J. P.; Davelaar, N.; Asmawidjaja, P.; Hazes, J. M.; Lubberts, E.
• Is Part Of: Annals of the rheumatic diseases. Volume 72:Supplement 3(2013)
• Page Start: A176
• Page End: A176
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-eular.564
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Th17 cells are critically involved in autoimmune disease induction and severity. Recently, we showed that Th17 cells, but not Th1 cells, from patients with rheumatoid arthritis (RA) upon interactionwith RA-synovial-fibroblasts (RASF) directly induced autocrine IL-17A production. This autocrine IL-17A production in turn creates a pro-inflammatory loop characterized by up-regulation of the pro-inflammatory cytokines IL-6 and IL-8, and the cartilage degrading enzymes MMP-1 and MMP-3. This loop may be an important pathway in the progression of an early inflammatory arthritis, towards a chronic destructive arthritis. However, the mechanism underlying the autocrine IL-17A production in the pro-inflammatory loop upon Th17-RASF interaction is currently unknown. Objectives: To investigate the mechanism responsible for the autocrine IL-17A induction upon Th17-RASF interaction. Methods: CD4+CD45RO+CCR6+ (Th17) and CD4+CD45RO+CCR6- (Th1) cells were isolated by FACS sorting from healthy controls and early RA patients. These cells were co-cultured with RASF, in the presence of neutralizing antibodies directed against soluble IL-6R (anti-sIL-6R), and/or IL-1β, and/or IL-23, etanercept, and celecoxib. Gene expression profiles were generated and supernatant was collected for cytokine analyses by ELISA. Results: IL-6, IL-1β and cyclooxygenase-2 (COX-2) expressions and prostaglandin-E2 (PGE2 ) production in Th17-RASF cultures were higher than in Th1-RASF cultures. Cytokine neutralization showed that IL-1β, IL-6 and IL-23 contributed marginally to the IL-17A induction. In contrast, treatment with celecoxib, a COX-2 inhibiter, resulted in significantly lower PGE2 and IL-17A production. This effect was IL-17A specific as no inhibitory effects were found on IFN-γ and TNF-α production. Combined celecoxib and TNF-α blockade more effectively suppressed the pro-inflammatory loop than did single treatment, as shown by lower IL-6, IL-8, matrix metalloproteinase-1 (MMP-1) and MMP-3 production. Conclusions: These findings show a critical role for the COX-2/PGE2 pathway in driving Th17-mediated synovial inflammation in an IL-23 and monocyte independent manner. Therefore, it would be important to control PGE2 in chronic inflammation in RA and other Th17-mediated autoimmune disorders. Disclosure of Interest: None Declared