Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2.
Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients. We hypothesized that luminal proteinases activate PAR-2 and induce colonic inflammation. Mice received intracolonically PAR-2 agonists (trypsin, tryptase, and a selective PAR-2-activating peptide) or control drugs (boiled enzymes, inactive peptide) and inflammatory parameters were followed at various times after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2 expression and induced an inflammatory reaction characterized by granulocyte infiltration, increased wall thickness, tissue damage, and elevated T-helper cell type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was resolved 48 hours after the intracolonic administration. PAR-2 activation also increased paracellular permeability of the colon and induced bacterial trans-location into peritoneal organs. These proinflammatory and pathophysiological changes observed in wild-type mice were not detected in PAR-2-deficient mice. Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are found at high levels in the colon lumen of patients with Crohn's disease or ulcerative colitis, our data may bear directly on the pathophysiology of human inflammatory bowel diseases.
Cenac
Nicolas
N
Neuro-Gastroenterology and Nutrition Unit, Institut National de la Recherche Agronomique, Toulouse, France.
Coelho
Anne-Marie
AM
Nguyen
Cathy
C
Compton
Steven
S
Andrade-Gordon
Patricia
P
MacNaughton
Wallace K
WK
Wallace
John L
JL
Hollenberg
Morley D
MD
Bunnett
Nigel W
NW
Garcia-Villar
Rafael
R
Bueno
Lionel
L
Vergnolle
Nathalie
N
D000818:Animals; D018988:Bacterial Translocation; D003092:Colitis / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D012333:RNA, Messenger / Q000096:biosynthesis; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases; D014357:Trypsin; D053802:Tryptases
D016207:Cytokines; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C509190:Tpsb2 protein, mouse; D012697:Serine Endopeptidases; D014357:Trypsin; C509222:Tpsab1 protein, mouse; D053802:Tryptases