Proteinase-activated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune response.
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.
Cenac
Nicolas
N
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Canada.
Cellars
Laurie
L
Steinhoff
Martin
M
Andrade-Gordon
Patricia
P
Hollenberg
Morley Donald
MD
Wallace
John Lawrence
JL
Fiorucci
Stefano
S
Vergnolle
Nathalie
N
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
D016207:Cytokines; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D010081:Oxazolone; D010975:Platelet Aggregation Inhibitors