Proteinase-activated receptor 2 is an anti-inflammatory signal for coloniclamina propria lymphocytes in a mouse model of colitis

The proteinase-activated receptor 2 (PAR-2) is a member of a family of G pr otein-coupled receptors for proteases. Proteases cleave PARs within the ext racellular N-terminal domains to expose tethered ligands that bind to and a ctivate the cleaved receptors. PAR-2 is highly expressed in colon in epithe lial and neuronal elements. In this study we show that PAR-2 activation pre vents the development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitr obenzene sulfonic acid (TNBS) in mice. A role for PAR-2 in the protection a gainst colon inflammation was explored by the use of SLIGRL-NH2, a syntheti c peptide that corresponds to the mouse tethered ligand exposed after PAR-2 cleavage. TNBS-induced colitis was dose-dependently reduced by the adminis tration of SLIGRL-NH2, whereas the scramble control peptide, LSIGRL-NH2, wa s un-effective. This beneficial effect was reflected by increased survival rates, improvement of macroscopic and histologic scores, decrease in mucosa l content of T helper cell type 1 cytokines, protein, and mRNA, and a dimin ished myeloperoxidase activity. SLIGRL-NH2, but not the scramble peptide, d irectly inhibited IFN-gamma secretion and CD44 expression on lamina propria T lymphocytes. Protection exerted by PAR-2 in TNBS-treated mice was revert ed by injecting mice with a truncated form of calcitonin gene-related pepti de and by sensory neurons ablation with the neurotoxin capsaicin. Collectiv ely, these studies show that PAR-2 is an anti-inflammatory receptor in the colon and suggest that PAR-2 ligands might be effective in the treatment of inflammatory bowel diseases.