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ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice.
- Source :
-
Gut [Gut] 2014 Oct; Vol. 63 (10), pp. 1587-95. Date of Electronic Publication: 2014 Jan 17. - Publication Year :
- 2014
-
Abstract
- Background: ClC-3 channel/antiporter plays a critical role in a variety of cellular activities. ClC-3 has been detected in the ileum and colon.<br />Objective: To determine the functions of ClC-3 in the gastrointestinal tract.<br />Design: After administration of dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), intestines from ClC-3-/- and wild-type mice were examined by histological, cellular, molecular and biochemical approaches. ClC-3 expression was determined by western blot and immunostaining.<br />Results: ClC-3 expression was reduced in intestinal tissues from patients with UC or Crohn's disease and from mice treated with DSS. Genetic deletion of ClC-3 increased the susceptibility of mice to DSS- or TNBS-induced experimental colitis and prevented intestinal recovery. ClC-3 deficiency promoted DSS-induced apoptosis of intestinal epithelial cells through the mitochondria pathway. ClC-3 interacts with voltage-dependent anion channel 1, a key player in regulation of mitochondria cytochrome c release, but DSS treatment decreased this interaction. In addition, lack of ClC-3 reduced the numbers of Paneth cells and impaired the expression of antimicrobial peptides. These alterations led to dysfunction of the epithelial barrier and invasion of commensal bacteria into the mucosa.<br />Conclusions: A defect in ClC-3 may contribute to the pathogenesis of IBD by promoting intestinal epithelial cell apoptosis and Paneth cell loss, suggesting that modulation of ClC-3 expression might be a new strategy for the treatment of IBD.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Subjects :
- Animals
Antiporters drug effects
Apoptosis
Blotting, Western
Colitis, Ulcerative chemically induced
Colitis, Ulcerative pathology
Crohn Disease pathology
Dextran Sulfate toxicity
Disease Models, Animal
Electrophoresis, Polyacrylamide Gel
Gastrointestinal Tract drug effects
Gastrointestinal Tract pathology
Humans
In Situ Nick-End Labeling
Mice
Mice, Inbred C57BL
Mice, Knockout
Trinitrobenzenesulfonic Acid toxicity
Antiporters metabolism
Chloride Channels physiology
Colitis, Ulcerative metabolism
Crohn Disease metabolism
Gastrointestinal Tract metabolism
Paneth Cells pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 63
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 24440986
- Full Text :
- https://doi.org/10.1136/gutjnl-2013-305168