title: Interleukin-13 stimulates MUC5AC expression via a STAT6-TMEM16A-ERK1/2 pathway in human airway epithelial cells.
abstract: Transmembrane protein 16A (TMEM16A), a channel underlying the calcium-activated chloride channel (CaCC) currents, has been shown to be a key regulator of mucus overproduction in airway epithelial cells. However, the precise molecular mechanism involved in the TMEM16A-mediated mucus secretion remains unclear. In the present study, we inquired into a novel signaling mechanism for TMEM16A driving mucin 5AC (MUC5AC) production in human airway epithelial cells. Following treatment for 24-48h with type 13 interleukin (IL-13), an upregulation of TMEM16A expression in both mRNA and protein levels was observed in human bronchial epithelial cell line (HBE16), while signal transducer and activator of transcription 6 (STAT6) inhibition could decrease this elevated expression, suggesting that the regulation of TMEM16A expression by IL-13 was via a STAT6-based transcriptional mechanism. Further investigation of the HBE16 cells revealed that TMEM16A knockdown or specific chloride channel inhibitor T16Ainh-A01 could suppress the CaCC currents and consequently reduce the extracellular regulated kinase (ERK1/2) phosphorylation, accompanying a dramatical decrease in MUC5AC expression. Moreover, pretreated with PD98059, an inhibitor of ERK1/2, the HB16 cells showed a remarkable diminution in TMEM16A-mediated MUC5AC expression. Altogether, STAT6-TMEM16A-ERK1/2 signal pathway and TMEM16A channel activity are required for the IL-13-induced TMEM16A mediated mucus production.
authors: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors: Yanling
authors: Y
authors: Qin
authors: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors: Youfan
authors: Y
authors: Jiang
authors: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors: Awais Shafiq
authors: AS
authors: Sheikh
authors: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors: Shanshan
authors: S
authors: Shen
authors: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors: Jing
authors: J
authors: Liu
authors: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China. Electronic address: depengjiang@sina.com.
authors: Depeng
authors: D
authors: Jiang
mesh_terms: D000075369:Anoctamin-1; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D055271:Mucin 5AC / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D018793:Interleukin-13; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human
keywords: Extracellular regulated kinase; Mucin 5AC; Signal transducer and activator of transcription 6; Transmembrane protein 16A