Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism.
Proteinase-activated receptor-2 (PAR2) activation induces colonic inflammation by an unknown mechanism. We hypothesized that PAR2 agonists administered intracolonically in mice induce inflammation via a neurogenic mechanism. Pretreatment of mice with neurokinin-1 and calcitonin-gene-related peptide (CGRP) receptor antagonists or with capsaicin showed attenuated PAR2-agonist-induced colitis. Immunohistochemistry demonstrated a differential expression of a marker for the type-1 CGRP receptor during the time course of PAR2-agonist-induced colitis, further suggesting a role for CGRP. We conclude that PAR2-agonist-induced intestinal inflammation involves the release of neuropeptides, which by acting on their receptors cause inflammation. These results implicate PAR2 as an important mediator of intestinal neurogenic inflammation.
Nguyen
Cathy
C
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
Coelho
Anne-Marie
AM
Grady
Eileen
E
Compton
Steven J
SJ
Wallace
John L
JL
Hollenberg
Morley D
MD
Cenac
Nicolas
N
Garcia-Villar
Rafael
R
Bueno
Lionel
L
Steinhoff
Martin
M
Bunnett
Nigel W
NW
Vergnolle
Nathalie
N
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology; D051379:Mice; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism
D009479:Neuropeptides; D009842:Oligopeptides; D010880:Piperidines; D011812:Quinuclidines; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; C085215:SR 140333; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin