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


METHODS
Colonic inflammation in wild-type and PAR(2)(-/-) 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 PAR(2)(-/-) mice. Changes in vessel leukocyte recruitment parameters (rolling and adhesion) were also significantly reduced in PAR(2)(-/-) 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 PAR(2)(-/-) mice challenged with TNBS-induced colitis.


CONCLUSIONS
The role of endogenous PAR(2) in the gut is pro-inflammatory and independent of the T helper-1 or -2 cytokine profile. Endogenous PAR(2) activation controls leukocyte recruitment in the colon and thus appears as a new potential therapeutic target for the treatment of inflammatory bowel disease.
Hyun
E
E
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Canada.
Andrade-Gordon
P
P
Steinhoff
M
M
Vergnolle
N
N
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D010081:Oxazolone; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D014302:Trinitrobenzenesulfonic Acid
D015815:Cell Adhesion Molecules; D044464:Receptor, PAR-2; D010081:Oxazolone; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase; D011451:Prostaglandin-Endoperoxide Synthases