Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: Ex vivo studies using a novel proteinase-activated receptor 2 antagonist

Kelso, E. B., Ferrell, W. R., Lockhart, J. C., Elias-Jones, I., Hembrough, T., Dunning, L., Gracie, J. A. and McInnes, I. B. (2007) Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: Ex vivo studies using a novel proteinase-activated receptor 2 antagonist. Arthritis and Rheumatism, 56(3), pp. 765-771. (doi: 10.1002/art.22423) (PMID:17328048)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McInnes, Professor Iain and Dunning, Mrs Lynette and Kelso, Mrs Elizabeth and Gracie, Professor Alastair and Ferrell, Professor William and Lockhart, Professor John
• Authors: Kelso, E. B., Ferrell, W. R., Lockhart, J. C., Elias-Jones, I., Hembrough, T., Dunning, L., Gracie, J. A., and McInnes, I. B.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Arthritis and Rheumatism
• Publisher: John Wiley & Sons, Inc.
• ISSN: 0004-3591
• ISSN (Online): 1529-0131
• Published Online: 27 February 2007