ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice.
Gut
; 63(10): 1587-95, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-24440986
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.OBJECTIVE:
To determine the functions of ClC-3 in the gastrointestinal tract.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.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.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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Colite Ulcerativa
/
Doença de Crohn
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Canais de Cloreto
/
Antiporters
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Celulas de Paneth
/
Trato Gastrointestinal
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Gut
Ano de publicação:
2014
Tipo de documento:
Article