Lin-Yan Huang1, Qing He2, Si-Jia Liang3, Ying-Xue Su3, Li-Xiong Xiong3, Qian-Qian Wu3, Qin-Yan Wu2, Jing Tao3, Jian-Ping Wang4, Yong-Bo Tang3, Xiao-Fei Lv3, Jie Liu3, Yong-Yuan Guan3, Rui-Ping Pang5, Jia-Guo Zhou3. 1. Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China School of Medical Technology, Xuzhou Medical College, Xuzhou, Jiagsu, China. 2. Gastrointestinal Institute, the 6th Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China. 3. Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China. 4. Department of Colorectal Surgery, The 6th Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China. 5. Department of Physiology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
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. 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.
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. 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.