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

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 2

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Immunohistolocalization of PAR1 protein expression in the muscularis muc...
Immunohistolocalization of PAR1 protein expression in the muscularis mucosae of human colon (A–D) and in whole colonic tissues from naive mice (E) and mice with TNBS-induced colitis (F–H). (A) Human biopsy section obtained from a macroscopically normal colon resected from a patient diagnosed with Crohn disease. PAR1 immunoreactivity was observed in vessels (arrows) and smooth muscle cells (arrowhead) (original magnification, ×100). (B) The same tissue incubated with a blocking peptide for the anti-PAR1 antibody (original magnification, ×100). PAR1 staining on the vessel was inhibited (arrow). (C) Tissues of the same patient collected in a macroscopically inflamed area, showing extensive necrosis and inflammatory infiltration of lamina propria by lymphomonocytic cells (inset) and PAR1-positive vessels (arrow). (D) A higher magnification (×400) of the vessel shown in C (arrows). Infiltrated inflammatory cells were observed in the lumen of the blood vessel. (E) Colonic tissues from naive mice, where PAR1 was expressed mainly on the epithelium (arrows). (F) Colonic tissues from TNBS-treated mice, with large tissue disruption, mucosal erosions (arrows), and PAR1 staining in infiltrated cells of the lamina propria (arrowheads) as well as epithelium. (G) The PAR1 antibody was preincubated with a blocking peptide at 20 μg/ml to show specificity (original magnification, ×40). (H) A higher magnification of infiltrated cells of the lamina propria (arrows and arrowheads) positively stained for PAR1 (original magnification, ×400).