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Epithelial expression and function of trypsin-3 in irritable bowel syndrome

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 si...

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Autores principales: Rolland-Fourcade, Claire, Denadai-Souza, Alexandre, Cirillo, Carla, Lopez, Cintya, Jaramillo, Josue Obed, Desormeaux, Cleo, Cenac, Nicolas, Motta, Jean-Paul, Larauche, Muriel, Taché, Yvette, Berghe, Pieter Vanden, Neunlist, Michel, Coron, Emmanuel, Kirzin, Sylvain, Portier, Guillaume, Bonnet, Delphine, Alric, Laurent, Vanner, Stephen, Deraison, Celine, Vergnolle, Nathalie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595105/
https://www.ncbi.nlm.nih.gov/pubmed/28096305
http://dx.doi.org/10.1136/gutjnl-2016-312094
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author Rolland-Fourcade, Claire
Denadai-Souza, Alexandre
Cirillo, Carla
Lopez, Cintya
Jaramillo, Josue Obed
Desormeaux, Cleo
Cenac, Nicolas
Motta, Jean-Paul
Larauche, Muriel
Taché, Yvette
Berghe, Pieter Vanden
Neunlist, Michel
Coron, Emmanuel
Kirzin, Sylvain
Portier, Guillaume
Bonnet, Delphine
Alric, Laurent
Vanner, Stephen
Deraison, Celine
Vergnolle, Nathalie
author_facet Rolland-Fourcade, Claire
Denadai-Souza, Alexandre
Cirillo, Carla
Lopez, Cintya
Jaramillo, Josue Obed
Desormeaux, Cleo
Cenac, Nicolas
Motta, Jean-Paul
Larauche, Muriel
Taché, Yvette
Berghe, Pieter Vanden
Neunlist, Michel
Coron, Emmanuel
Kirzin, Sylvain
Portier, Guillaume
Bonnet, Delphine
Alric, Laurent
Vanner, Stephen
Deraison, Celine
Vergnolle, Nathalie
author_sort Rolland-Fourcade, Claire
collection PubMed
description 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 Ca(2+) 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.
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spelling pubmed-55951052017-09-20 Epithelial expression and function of trypsin-3 in irritable bowel syndrome Rolland-Fourcade, Claire Denadai-Souza, Alexandre Cirillo, Carla Lopez, Cintya Jaramillo, Josue Obed Desormeaux, Cleo Cenac, Nicolas Motta, Jean-Paul Larauche, Muriel Taché, Yvette Berghe, Pieter Vanden Neunlist, Michel Coron, Emmanuel Kirzin, Sylvain Portier, Guillaume Bonnet, Delphine Alric, Laurent Vanner, Stephen Deraison, Celine Vergnolle, Nathalie Gut Neurogastroenterology 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 Ca(2+) 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. BMJ Publishing Group 2017-10 2017-01-17 /pmc/articles/PMC5595105/ /pubmed/28096305 http://dx.doi.org/10.1136/gutjnl-2016-312094 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
spellingShingle Neurogastroenterology
Rolland-Fourcade, Claire
Denadai-Souza, Alexandre
Cirillo, Carla
Lopez, Cintya
Jaramillo, Josue Obed
Desormeaux, Cleo
Cenac, Nicolas
Motta, Jean-Paul
Larauche, Muriel
Taché, Yvette
Berghe, Pieter Vanden
Neunlist, Michel
Coron, Emmanuel
Kirzin, Sylvain
Portier, Guillaume
Bonnet, Delphine
Alric, Laurent
Vanner, Stephen
Deraison, Celine
Vergnolle, Nathalie
Epithelial expression and function of trypsin-3 in irritable bowel syndrome
title Epithelial expression and function of trypsin-3 in irritable bowel syndrome
title_full Epithelial expression and function of trypsin-3 in irritable bowel syndrome
title_fullStr Epithelial expression and function of trypsin-3 in irritable bowel syndrome
title_full_unstemmed Epithelial expression and function of trypsin-3 in irritable bowel syndrome
title_short Epithelial expression and function of trypsin-3 in irritable bowel syndrome
title_sort epithelial expression and function of trypsin-3 in irritable bowel syndrome
topic Neurogastroenterology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595105/
https://www.ncbi.nlm.nih.gov/pubmed/28096305
http://dx.doi.org/10.1136/gutjnl-2016-312094
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