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

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

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)1444-1456
Number of pages13
JournalJournal of Clinical Investigation
Volume114
Issue number10
DOIs
StatePublished - Nov 2004

ASJC Scopus subject areas

  • Medicine(all)

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    Vergnolle, N., Cellars, L., Mencarelli, A., Rizzo, G., Swaminathan, S., Beck, P., Steinhoff, M., Andrade-Gordon, P., Bunnett, N. W., Hollenberg, M. D., Wallace, J. L., Cirino, G., & Fiorucci, S. (2004). A role for proteinase-activated receptor-1 in inflammatory bowel diseases. Journal of Clinical Investigation, 114(10), 1444-1456. https://doi.org/10.1172/JCI21689