Proteinase-activated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune response

Background: Activation of colonic proteinase activated receptor-1 (PAR,) provokes colonic inflammation and increases mucosal permeability in mice. The mechanism of inflammation is not neurogenic like in the paw of rats but depends on PAR(1)-mediated activation monocytic cells. PAR, activation in the colon increases the release of lymphocyte T helper-1 (T(H)1) cytokines. Moreover, PAR, expression is increased in biopsies from patients with inflammatory bowel disease, and its activation during T(H)1-mediated colitis in mice increases all of the hallmarks of inflammation. Methods: This study aimed to characterize the effects of PAR, activation in oxazolone-mediated colitis, involving a T(H)2 cytokine profile. Results: Intracolonic administration of oxazolone increased myeloperoxidase activity, damage score, and interleukin (IL)-4, IL-10, tumor necrosis factor alpha, and lL-IP mRNA expression but lowered interferon-gamma mRNA expression, indicating colonic inflammation of a T(H)2 profile. The concurrent intracolonic administration of a PAR, agonist in oxazolone-treated mice inhibited colitis, resulting in a reduction of myeloperoxidase activity, damage score, and inflammatory cytokine mRNA expression. Using PAR(1)-deficient mice, we confirmed that the anti-inflammatory effects of PAR(1) agonists were mediated by PAR,. Moreover, in PAR(1)-deficient mice or in mice treated with a PAR, antagonist, oxazolone-induced colitis was exacerbated, showing an endogenous modulatory role for PAR, in this TH2 cytokine profile of colitis. Conclusions: Thus, as opposed to a previously shown proinflammatory role for PAR(1) in a T(H)1 cytokine-mediated colitis, our new data show anti-inflammatory role for PAR, activation in the setting of T(H)2 cytokine colitis model.