Intestinal inflammation

Protease-activated receptor-2 activation: a major actor in intestinal inflammation

E Hyun¹, P Andrade-Gordon², M Steinhoff³, N Vergnolle^1,4,5

¹ Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Canada
² Johnson & Johnson Pharmaceutical Research & Development, Spring House Pennsylvania, USA
³ Department of Dermatology and Interdisciplinary Center for Clinical Research, Münster, University of Münster, Germany
⁴ INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
⁵ Université Toulouse III Paul Sabatier, Toulouse, France

Dr N Vergnolle, INSERM U563, BP 3028, CHU Purpan, 31024 Toulouse Cedex, France; nathalie.vergnolle{at}inserm.fr

Background and aims: The role of protease-activated receptor-2 (PAR₂) during intestinal inflammation is still unclear due to the fact that PAR₂-activating peptide has both pro- and anti-inflammatory properties. The aim of this study was to investigate the effects of PAR₂ deficiency (using PAR₂-deficient mice, PAR₂^–/–) in models of colitis, in order to elucidate the role of endogenous PAR₂ in the process of inflammation in the gut.

Methods: Colonic inflammation in wild-type and PAR₂^–/– mice was induced by dextran sodium sulfate, trinitrobenzene sulfonic acid (TNBS), a T helper-1 predominant model, or oxazolone, a T helper-2 predominant model. Leukocyte recruitment, assessed by intravital microscopy, and inflammatory parameters (myeloperoxidase (MPO), macroscopic and microscopic damage) were assessed during the development of colitis. Lastly, the protein levels of cyclooxygenases (COXs) and adhesion molecules (ICAM-1, VCAM-1, alpha-M, alpha-4) were assessed by using western blot analysis.

Results: In all three models of colitis, MPO activity, macroscopic damage score and bowel thickness were significantly lower in PAR₂^–/– mice. Changes in vessel leukocyte recruitment parameters (rolling and adhesion) were also significantly reduced in PAR₂^–/– mice compared to wild-type mice after the induction of colitis. The protein expression of ICAM-1, VCAM-1 and alpha-4 was significantly attenuated, whereas the expression of COX-1 was significantly increased in PAR₂^–/– mice challenged with TNBS-induced colitis.

Conclusions: The role of endogenous PAR₂ in the gut is pro-inflammatory and independent of the T helper-1 or -2 cytokine profile. Endogenous PAR₂ activation controls leukocyte recruitment in the colon and thus appears as a new potential therapeutic target for the treatment of inflammatory bowel disease.

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