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A3.17 Synovial Fibroblasts Directly Induce Th17 Pathogenicity via the Cyclooxygenase/Prostaglandin-E2 Pathway, Independent of IL-23
  1. Sandra MJ Paulissen1,2,
  2. Jan Piet van Hamburg1,2,
  3. Nadine Davelaar1,2,
  4. Patrick S Asmawidjaja1,2,
  5. Johanna MW Hazes1,2,
  6. Erik Lubberts1
  1. 1Department of Rheumatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
  2. 2Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands


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 interaction with RA-synovial-fibroblasts (RASF) directly induced autocrine IL-17A production. This autocrine IL-17A production in turn creates a pro-inflammatory loop characterised 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.

Materials and 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 neutralising 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 neutralisation 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.

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