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A role for proteinase-activated receptor–1 in inflammatory bowel diseases
Nathalie Vergnolle, … , Giuseppe Cirino, Stefano Fiorucci
Nathalie Vergnolle, … , Giuseppe Cirino, Stefano Fiorucci
Published November 15, 2004
Citation Information: J Clin Invest. 2004;114(10):1444-1456. https://doi.org/10.1172/JCI21689.
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Article Immunology

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

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Abstract

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.

Authors

Nathalie Vergnolle, Laurie Cellars, Andrea Mencarelli, Giovanni Rizzo, Sunita Swaminathan, Paul Beck, Martin Steinhoff, Patricia Andrade-Gordon, Nigel W. Bunnett, Morley D. Hollenberg, John L. Wallace, Giuseppe Cirino, Stefano Fiorucci

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Figure 1

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PAR1 mRNA detection in humans and mice. (A and B) PAR1 mRNA detection in...
PAR1 mRNA detection in humans and mice. (A and B) PAR1 mRNA detection in colonic biopsies from control (normal), ulcerative colitis (UC), or Crohn disease (CD) patients, by RT-PCR (A) and real-time RT-PCR (B). A minimum of 5 patients per group was considered for quantification, and representative RT-PCR for 3 patients per group is shown (blots). hPAR1, human PAR1. (C) PAR1 mRNA detection in colonic tissues from naive mice or mice with TNBS- or DSS-induced colitis. PAR1 mRNA detection was assessed by the amplification of a specific PCR fragment and was expressed as percentage of amplified GAPDH fragment. For quantification, values are mean ± SEM; n = 5 per group. *P < 0.05, **P < 0.01, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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