Interleukin-13 Stimulates MUC5AC Expression Via A STAT6-TMEM16A-ERK1/2 Pathway In Human Airway Epithelial Cells

Transmembrane protein 16A(TMEM16A),a channel underlying t he calcium-activated Chloride channel(Ca CC)currents,has been sho wn to be a key regulator of mucus overproduction in airway epitheli al 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 TMEM16 A driving mucin 5AC(MUC5AC)production in human airway epithelial cells(HBE16).Following treatment for 24-48 hours with type 13 In terleukin(IL-13),an upregulation of TMEM16 A expression in both m RNA and protein levels was observed in HBE16,while signal transd ucer and activator of transcription 6(STAT6)inhibition AS1517499 c ould decrease this elevated expression,suggesting that the regulation of TMEM16 A expression by IL-13 was via a STAT6-based transcripti onal mechanism.Further investigation of the HBE16 cells transfected with TMEM16 A plasmid revealed that the expression of TMEM16A was increased,and the activation of extracellular signal regulated kinase(ERK1/2)was enhanced.However,TMEM16 A knockdown or spe cific chloride channel inhibitor T16Ainh-A01 in HBE16 cell could supp ress the expression of TMEM16 A and consequently reduce ERK1/2 phosphorylation,accompanying a dramatical decrease in MUC5 AC ex pression.Moreover,pretreated with PD98059,an inhibitor of ERK1/2,the HB16 cells showed a remarkable diminution in TMEM16A-medi ated MUC5 AC expression.Altogether,STAT6-TMEM16A-ERK1/2 sign al pathway and TMEM16 A channel activity are required for the IL-13-induced TMEM16 A mediated mucus production.