TMEM16A is a Ca²⁺-activated chloride channel that was shown to enhance production and secretion of mucus in inflamed airways. It is, however, not clear whether TMEM16A directly supports mucus production, or whether mucin and TMEM16A are upregulated independently during inflammatory airway diseases such as asthma and cystic fibrosis (CF). We examined this question using BCi-NS1 cells, a human airway basal cell line that maintains multipotent differentiation capacity, and the two human airway epithelial cell lines, Calu-3 and CFBE. The data demonstrate that exposure of airway epithelial cells to IL-8 and IL-13, two cytokines known to be enhanced in CF and asthma, respectively, leads to an increase in mucus production. Expression of MUC5AC was fully dependent on expression of TMEM16A, as shown by siRNA knockdown of TMEM16A. In addition, different inhibitors of TMEM16A attenuated IL-13–induced mucus production. Interestingly, in CFBE cells expressing F508 delCFTR, IL-13 was unable to upregulate membrane expression of TMEM16A or Ca²⁺-activated whole cell currents. The regulator of TMEM16A, CLCA1, strongly augmented both Ca²⁺- and cAMP-activated Cl⁻ currents in cells expressing wtCFTR but failed to augment membrane expression of TMEM16A in F508 delCFTR-expressing CFBE cells. The data confirm the functional relationship between CFTR and TMEM16A and suggest an impaired upregulation of TMEM16A by IL-13 or CLCA1 in cells expressing the most frequent CF-causing mutation F508 delCFTR.

TMEM16A是Ca ²⁺激活的氯离子通道，可增强发炎的气道中粘液的产生和分泌。但是，尚不清楚TMEM16A是否直接支持粘液产生，或者在哮喘和囊性纤维化（CF）等发炎性气道疾病期间，粘蛋白和TMEM16A是否独立上调。我们使用BCi-NS1细胞（一种维持多能分化能力的人气道基础细胞系）以及两种人气道上皮细胞系Calu-3和CFBE检查了这个问题。数据表明，气道上皮细胞暴露于IL-8和IL-13（两种分别已知在CF和哮喘中得到增强的细胞因子）会导致粘液产生增加。MUC5AC的表达完全依赖于TMEM16A的表达，如TMEM16A的siRNA敲除所示。此外，TMEM16A的不同抑制剂减弱了IL-13诱导的粘液产生。有趣的是，在表达F508 delCFTR的CFBE细胞中，IL-13不能上调TMEM16A或Ca的膜表达²⁺激活的整个电池电流。TMEM16A，CLCA1所述的调节器，强烈增强二者的Ca ²⁺ -和cAMP激活的氯^-电流在表达wtCFTR细胞，但未能在F508 delCFTR表达CFBE细胞TMEM16A的扩充膜表达。数据证实了CFTR和TMEM16A之间的功能关系，并暗示了IL-13或CLCA1在表达最常见CF引起的突变F508 delCFTR的细胞中损害了TMEM16A的上调。