Par-2 in the pathogenesis of collagen-induced arthritis: crucial role in T cell differentiation

Protease-activated receptor-2 (PAR-2) is a member of a novel family of seven-transmembrane G-protein-coupled receptors (PARs) activated by proteolytic cleavage to reveal a tethered ligand. Serine proteases such as mast cell tryptase cleave PAR-2 at a specific site within the extracellular N-terminus to expose a new N-terminal tethered ligand domain, which binds to and thereby activates the cleaved receptor. We previously demonstrated that adjuvant monoarthritis is substantially inhibited in PAR-2 'knockout' mice (1). The present study extended these earlier finding by investigating the therapeutic potential of a novel PAR-2 antagonist, ENMD-1068, in the murine model of collagen-induced arthritis (CIA); we recently demonstrated this antagonist inhibited TNF generation from the synovial membrane of RA patients (2). We further tested the hypothesis that this receptor contributes to the pathogenesis of arthritis by affecting T lymphocyte activation and/or differentiation to Th1, Th2 and Th17 phenotypes.