Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism

Abstract

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.Key words: trypsin, proteinase-activated receptor-2, colitis, neurogenic inflammation, substance P, neurokinin-1 receptors, calcitonin-gene-related peptide.