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

E Hyun1, P Andrade-Gordon, M Steinhoff

  • 1Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Canada.

Gut
|May 8, 2008
PubMed
Abstract

Insights

Protease-activated receptor-2 (PAR(2)) plays a pro-inflammatory role in gut inflammation. PAR(2) deficiency reduces inflammation and leukocyte recruitment, suggesting it as a therapeutic target for inflammatory bowel disease.

Area of Science:

  • Gastroenterology
  • Immunology
  • Molecular Biology

Background:

  • The role of protease-activated receptor-2 (PAR(2)) in intestinal inflammation is complex, with conflicting evidence regarding its pro- or anti-inflammatory effects.
  • Investigating PAR(2) deficiency in mouse models is crucial to understand the function of endogenous PAR(2) in gut inflammation.

Purpose of the Study:

  • To elucidate the role of endogenous PAR(2) in the development of colitis.
  • To determine if PAR(2) deficiency impacts inflammatory responses in different models of intestinal inflammation.

Main Methods:

  • Induction of colitis in wild-type and PAR(2)-deficient mice using dextran sodium sulfate, trinitrobenzene sulfonic acid (TNBS), or oxazolone.
  • Assessment of leukocyte recruitment, myeloperoxidase (MPO) activity, and tissue damage.
  • Analysis of cyclooxygenase (COX) and adhesion molecule (ICAM-1, VCAM-1, alpha-M, alpha-4) protein expression via western blot.

Main Results:

  • PAR(2)-deficient mice exhibited significantly reduced MPO activity, macroscopic damage, and bowel thickness across all colitis models.
  • Leukocyte rolling and adhesion in the colon were significantly decreased in PAR(2)-deficient mice.
  • TNBS-induced colitis showed attenuated ICAM-1, VCAM-1, and alpha-4 expression, but increased COX-1 expression in PAR(2)-deficient mice.

Conclusions:

  • Endogenous PAR(2) activation has a pro-inflammatory role in the gut, independent of T helper-1 or -2 profiles.
  • PAR(2) controls leukocyte recruitment in the colon, identifying it as a potential therapeutic target for inflammatory bowel disease (IBD).

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