Submitted on March 27, 2007
Accepted on September 11, 2007
Involvement of Chloride Channels in TGF-
1-induced Apoptosis of Human Bronchial Epithelial Cells
Gang Cheng1, Zhifei Shao2, Bharti R. Chaudhari2, and Devendra K. Agrawal3*
1 Biomedical Sciences and Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, United States
2 Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska, United States
3 Biomedical Sciences, Internal Medicine, Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska, United States
* To whom correspondence should be addressed. E-mail: dkagr{at}creighton.edu.
Widespread damage of airway epithelium and defective epithelial repair are hallmarks of chronic asthma. Growth factors and cytokines spatially and temporally regulate epithelial shedding and repair. Within this context, a key function is exerted by transforming growth factor-beta (TGF-
). Recent growing evidence suggests that chloride (Cl-) channels are critical to cell apoptosis. We examined the effects of TGF-1 on Cl- channel expression and activity, and its relationship with apoptosis in human bronchial epithelial cells (HBECs). The siRNA approach was used to investigate the potential role of ClC-3, a member of the volume-regulated Cl- channel family, in apoptosis of HBECs. TGF-1 significantly induced HBEC apoptosis, which paralleled to a significant decrease in the endogenous expression of ClC-3 protein and mRNA transcripts. Outward rectifying and voltage-dependent ClC-3-like Cl- currents in HBECs were diminished by TGF-1. siRNA for ClC-3 abolished Cl- current and enhanced TGF-1-induced cell apoptosis. Overexpression of ClC-3 in HBECs inhibited TGF-1-induced cell apoptosis. Bcl-2 was also down-regulated after TGF- stimulation. TGF-1-induced cell apoptosis was suppressed in Bcl-2-transfected HBECs. Our data demonstrate that ClC-3-like voltage-gated chloride channels play an important role in TGF--induced apoptosis of human airway epithelial cells.
