ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice.
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.


METHODS
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.
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China School of Medical Technology, Xuzhou Medical College, Xuzhou, Jiagsu, China.
Lin-Yan
LY
Huang
Gastrointestinal Institute, the 6th Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Qing
Q
He
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Si-Jia
SJ
Liang
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Ying-Xue
YX
Su
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Li-Xiong
LX
Xiong
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Qian-Qian
QQ
Wu
Gastrointestinal Institute, the 6th Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Qin-Yan
QY
Wu
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Jing
J
Tao
Department of Colorectal Surgery, The 6th Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Jian-Ping
JP
Wang
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Yong-Bo
YB
Tang
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Xiao-Fei
XF
Lv
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Jie
J
Liu
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Yong-Yuan
YY
Guan
Department of Physiology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Rui-Ping
RP
Pang
Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Jia-Guo
JG
Zhou
D000818:Animals; D017920:Antiporters / Q000187:drug effects / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D018118:Chloride Channels / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019879:Paneth Cells / Q000473:pathology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D017920:Antiporters; D018118:Chloride Channels; C115376:ClC-3 channel; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate