RT Journal Article
SR Electronic
T1 Epithelial expression and function of trypsin-3 in irritable bowel syndrome
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1767
OP 1778
DO 10.1136/gutjnl-2016-312094
VO 66
IS 10
A1 Claire Rolland-Fourcade
A1 Alexandre Denadai-Souza
A1 Carla Cirillo
A1 Cintya Lopez
A1 Josue Obed Jaramillo
A1 Cleo Desormeaux
A1 Nicolas Cenac
A1 Jean-Paul Motta
A1 Muriel Larauche
A1 Yvette Taché
A1 Pieter Vanden Berghe
A1 Michel Neunlist
A1 Emmanuel Coron
A1 Sylvain Kirzin
A1 Guillaume Portier
A1 Delphine Bonnet
A1 Laurent Alric
A1 Stephen Vanner
A1 Celine Deraison
A1 Nathalie Vergnolle
YR 2017
UL http://gut.bmj.com/content/66/10/1767.abstract
AB Objectives Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity.Design Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (PRSS1, 2 and 3) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca2+ imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3.Results We showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism.Conclusions In IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.