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

Nov 17, 2004The Journal of clinical investigation

Proteinase-Activated Receptor-1 May Play a Role in Inflammatory Bowel Diseases

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Abstract

PAR1 is overexpressed in the colon of inflammatory bowel disease (IBD) patients.

PAR1 activation in the colon may be involved in the pathogenesis of IBD.
Intracolonic administration of PAR1 agonists in mice caused inflammation characterized by edema and granulocyte infiltration.
The inflammatory response induced by PAR1 activation was dependent on B and T lymphocytes.
In a mouse model of IBD, PAR1 activation exacerbated and prolonged inflammation.
PAR1 antagonism significantly decreased mortality and severity of colonic inflammation in mouse models.
Colitis development was strongly reduced in mice lacking PAR1.

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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 PAR1 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 PAR1 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.

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

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