Expression and pro-inflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies suing a novel proteinase-activated receptor-2 antagonist.

Elizabeth. B. Kelso, William R. Ferrell, John Lockhart, Iona Elias-Jones, Todd Hembrough, Lynette Dunning, J.Alistair Gracie, Iain B. McInness

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)765-771
Number of pages7
JournalArthritis & Rheumatology
Volume56
Issue number3
DOIs
Publication statusPublished - 2007

Keywords

  • PAR2
  • Rheumatoid arthritis

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