期刊
GUT
卷 63, 期 10, 页码 1587-1595出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2013-305168
关键词
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资金
- GDUPS
- National Natural Science Foundation of China [81273500, 30973536]
- National Basic Research Program of China [2009CB521903]
- National Research Foundation for the Doctoral Program of Higher Education of China [20120171110058]
- Natural Science Foundation of Guangdong Province [10451008901004539]
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.
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