TMEM16A Mediates The Hypersecretion Of Mucus Induced By Interleukin-13

Previous studies showed that the Ca2+-activated Cl- channel (Ca CC) was involved in the pathogenesis of mucus hypersecretion indu ced by Interleukin-13 (IL-13). However, the mechanisms underlying the process were unknown. Recently, transmembrane protein 16A (T MEM16A) was identified as the channel underlying the CACC curr ent. The aim of the current study was to investigate whether the T MEM16A channel is part of the mechanism underlying IL-13-induce d mucus hypersecretion. We observed that both TMEM16A mRNA and protein expression were significantly up-regulated after treatment with IL-13 in human bronchial epithelial 16(HBE 16) cells, which correlated with an increase in mucus production. Niflumic acid (N A), a selective antagonist of CaCC, markedly blocked IL-13-induced mucin (MUC) 5AC mRNA and protein production in vitro. Further investigation with HBE16 cells revealed that TMEM16A overexpre ssion clearly promoted mucus production, IκBα phosphorylation, and p65 accumulation in the nucleus. The loss of TMEM16A resulted in inhibition of mucus production, and the TMEM16A-mediated pro duction of MUC 5AC was significantly blocked by a nuclear factor-kappa B (NF-κB) inhibitor. Therefore, the TMEM16A channel acts upstream of NF-κB in the regulation of mucus production. This is the first demonstration that the TMEM16A-NF-κB pathway is posit ively involved in IL-13-induced mucus production, which provides n ovel insight into the molecular mechanism of mucin overproduction.