A role for proteinase-activated receptor-1 in inflammatory bowel diseases

Proteinase-activated receptor-1 (PAR₁), a G protein-coupled receptor activated by thrombin, is highly expressed in different cell types of the gastrointestinal tract. The activity of thrombin and of other proteinases is significantly increased in the colon of inflammatory bowel disease (IBD) patients. Since PAR₁ activation in tissues other than the gut provoked inflammation, we hypothesized that PAR₁ activation in the colon is involved in the pathogenesis of IBD. Here, we demonstrate that PAR ₁ is overexpressed in the colon of IBD patients. In mice, intracolonic administration of PAR₁ agonists led to an inflammatory reaction characterized by edema and granulocyte infiltration. This PAR ₁ activation-induced inflammation was dependent on B and T lymphocytes. Moreover, PAR₁ activation exacerbated and prolonged inflammation in a mouse model of IBD induced by the intracolonic administration of trinitrobenzene sulfonic acid (TNBS), while PAR₁ antagonism significantly decreased the mortality and severity of colonic inflammation induced by TNBS and dextran sodium sulfate. In these 2 models, colitis development was strongly attenuated by PAR₁ deficiency. Taken together, these results imply an important role for PAR₁ in the pathogenesis of experimental colitis, supporting the notion that PAR₁ inhibition may be beneficial in the context of IBD and possibly in other chronic intestinal inflammatory disorders.