title: Involvement of chloride channels in TGF-beta1-induced apoptosis of human bronchial epithelial cells.
abstract: 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 (TGF)-beta. Recent growing evidence suggests that chloride (Cl(-)) channels are critical to cell apoptosis. We examined the effects of TGF-beta1 on Cl(-) channel expression and activity and its relationship with apoptosis in human bronchial epithelial cells (HBECs). The small interfering RNA (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-beta1 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-beta1. siRNA for CLC-3 abolished Cl(-) current and enhanced TGF-beta1-induced cell apoptosis. Overexpression of CLC-3 in HBECs inhibited TGF-beta1-induced cell apoptosis. Bcl-2 was also downregulated after TGF-beta stimulation. TGF-beta1-induced cell apoptosis was suppressed in Bcl-2-transfected HBECs. Our data demonstrate that CLC-3-like voltage-gated chloride channels play a critical role in TGF-beta-induced apoptosis of human airway epithelial cells.
authors.affiliation: Department of Biomedical Sciences, Creighton Univ. School of Medicine, CRISS II Rm. 510, 2500 California Plaza, Omaha, NE 68178, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Shao
authors.forename: Bharti
authors.initials: B
authors.lastname: Chaudhari
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018118:Chloride Channels / Q000096:biosynthesis / Q000235:genetics*; D002712:Chlorides / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D018118:Chloride Channels; D002712:Chlorides; C115376:ClC-3 channel; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1