A role for proteinase-activated receptor-1 in inflammatory bowel diseases.
Proteinase-activated receptor-1 (PAR1), a G protein-coupled receptor activated by thrombin, is highly expressed in different cell types of the gastrointestinal tract. The activity of thrombin and of other proteinases is significantly increased in the colon of inflammatory bowel disease (IBD) patients. Since PAR1 activation in tissues other than the gut provoked inflammation, we hypothesized that PAR1 activation in the colon is involved in the pathogenesis of IBD. Here, we demonstrate that PAR1 is overexpressed in the colon of IBD patients. In mice, intracolonic administration of PAR1 agonists led to an inflammatory reaction characterized by edema and granulocyte infiltration. This PAR1 activation-induced inflammation was dependent on B and T lymphocytes. Moreover, PAR1 activation exacerbated and prolonged inflammation in a mouse model of IBD induced by the intracolonic administration of trinitrobenzene sulfonic acid (TNBS), while PAR1 antagonism significantly decreased the mortality and severity of colonic inflammation induced by TNBS and dextran sodium sulfate. In these 2 models, colitis development was strongly attenuated by PAR1 deficiency. Taken together, these results imply an important role for PAR1 in the pathogenesis of experimental colitis, supporting the notion that PAR1 inhibition may be beneficial in the context of IBD and possibly in other chronic intestinal inflammatory disorders.
Vergnolle
Nathalie
N
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada. nvergnol@ucalgary.ca
Cellars
Laurie
L
Mencarelli
Andrea
A
Rizzo
Giovanni
G
Swaminathan
Sunita
S
Beck
Paul
P
Steinhoff
Martin
M
Andrade-Gordon
Patricia
P
Bunnett
Nigel W
NW
Hollenberg
Morley D
MD
Wallace
John L
JL
Cirino
Giuseppe
G
Fiorucci
Stefano
S
D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000633:toxicity; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000378:metabolism*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D010446:Peptide Fragments; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase; D013917:Thrombin