title: Proteinase-activated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune response.
abstract: BACKGROUND
  Activation of colonic proteinase activated receptor-1 (PAR1) provokes colonic inflammation and increases mucosal permeability in mice. The mechanism of inflammation is not neurogenic like in the paw of rats but depends on PAR1-mediated activation monocytic cells. PAR1 activation in the colon increases the release of lymphocyte T helper-1 (TH1) cytokines. Moreover, PAR1 expression is increased in biopsies from patients with inflammatory bowel disease, and its activation during TH1-mediated colitis in mice increases all of the hallmarks of inflammation.
  
  
  METHODS
  This study aimed to characterize the effects of PAR1 activation in oxazolone-mediated colitis, involving a TH2 cytokine profile.
  
  
  RESULTS
  Intracolonic administration of oxazolone increased myeloperoxidase activity, damage score, and interleukin (IL)-4, IL-10, tumor necrosis factor alpha, and IL-1beta mRNA expression but lowered interferon-gamma mRNA expression, indicating colonic inflammation of a TH2 profile. The concurrent intracolonic administration of a PAR1 agonist in oxazolone-treated mice inhibited colitis, resulting in a reduction of myeloperoxidase activity, damage score, and inflammatory cytokine mRNA expression. Using PAR1-deficient mice, we confirmed that the anti-inflammatory effects of PAR1 agonists were mediated by PAR1. Moreover, in PAR1-deficient mice or in mice treated with a PAR1 antagonist, oxazolone-induced colitis was exacerbated, showing an endogenous modulatory role for PAR1 in this TH2 cytokine profile of colitis.
  
  
  CONCLUSIONS
  Thus, as opposed to a previously shown proinflammatory role for PAR1 in a TH1 cytokine-mediated colitis, our new data show anti-inflammatory role for PAR1 activation in the setting of TH2 cytokine colitis model.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.forename: Laurie
authors.initials: L
authors.lastname: Cellars
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Morley Donald
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: John Lawrence
authors.initials: JL
authors.lastname: Wallace
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000503:physiopathology* / Q000662:veterinary; D016207:Cytokines / Q000276:immunology; D007249:Inflammation / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010081:Oxazolone; D012333:RNA, Messenger / Q000096:biosynthesis; D044463:Receptor, PAR-1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D010975:Platelet Aggregation Inhibitors
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D010081:Oxazolone; D010975:Platelet Aggregation Inhibitors