Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: Ex vivo studies using a novel proteinase-activated receptor 2 antagonist
✍ Scribed by Elizabeth B. Kelso; William R. Ferrell; John C. Lockhart; Iona Elias-Jones; Todd Hembrough; Lynette Dunning; J. Alastair Gracie; Iain B. McInnes
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 221 KB
- Volume
- 56
- Category
- Article
- ISSN
- 0004-3591
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✦ Synopsis
Abstract
Objective
Serine proteinases activate the G protein–coupled receptor, proteinase‐activated receptor 2 (PAR‐2), via cleavage and exposure of a tethered ligand. PAR‐2 is known to exert proinflammatory actions in a murine model of arthritis, since PAR‐2–deficient mice exhibit strikingly reduced articular inflammation. This study was undertaken to examine synovial PAR‐2 expression and to determine the effect of a novel PAR‐2 antagonist on synovial cytokine production, in order to investigate the hypothesis that PAR‐2 plays a critical role in the pathogenesis of rheumatoid arthritis (RA).
Methods
Using a monoclonal antibody to human PAR‐2, expression in RA synovium and cultured synovial fibroblasts was characterized. The novel PAR‐2 antagonist, ENMD‐1068, was added to primary cultures of RA synovial tissue, from which spontaneous cytokine release was measured.
Results
PAR‐2 was substantially up‐regulated in RA synovium compared with control synovial tissue from patients with osteoarthritis or seronegative inflammatory arthritis, neither of which exhibited significant PAR‐2 expression. Importantly, spontaneous release of tumor necrosis factor α and interleukin‐1β from RA synovium was substantially inhibited by ENMD‐1068, in a dose‐dependent manner.
Conclusion
These findings identify PAR‐2 as a novel upstream regulator of proinflammatory cytokine production in RA and indicate its potential as a novel therapeutic target in inflammatory arthritis.