Gorrieri Giulia, Scudieri Paolo, Caci Emanuela, Schiavon Marco, Tomati Valeria, Sirci Francesco, Napolitano Francesco, Carrella Diego, Gianotti Ambra, Musante Ilaria, Favia Maria, Casavola Valeria, Guerra Lorenzo, Rea Federico, Ravazzolo Roberto, Di Bernardo Diego, Galietta Luis J V
U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy.
Department of Thoracic Surgery, University of Padova, Italy.
Sci Rep. 2016 Oct 27;6:36016. doi: 10.1038/srep36016.
Goblet cell hyperplasia, a feature of asthma and other respiratory diseases, is driven by the Th-2 cytokines IL-4 and IL-13. In human bronchial epithelial cells, we find that IL-4 induces the expression of many genes coding for ion channels and transporters, including TMEM16A, SLC26A4, SLC12A2, and ATP12A. At the functional level, we find that IL-4 enhances calcium- and cAMP-activated chloride/bicarbonate secretion, resulting in high bicarbonate concentration and alkaline pH in the fluid covering the apical surface of epithelia. Importantly, mucin release, elicited by purinergic stimulation, requires the presence of bicarbonate in the basolateral solution and is defective in cells derived from cystic fibrosis patients. In conclusion, our results suggest that Th-2 cytokines induce a profound change in expression and function in multiple ion channels and transporters that results in enhanced bicarbonate transport ability. This change is required as an important mechanism to favor release and clearance of mucus.
杯状细胞增生是哮喘和其他呼吸系统疾病的一个特征，由Th-2细胞因子白细胞介素-4（IL-4）和白细胞介素-13驱动。在人支气管上皮细胞中，我们发现IL-4可诱导许多编码离子通道和转运蛋白的基因表达，包括跨膜蛋白16A（TMEM16A）、溶质载体家族26成员4（SLC26A4）、溶质载体家族12成员2（SLC12A2）和ATP酶12A（ATP12A）。在功能水平上，我们发现IL-4可增强钙和环磷酸腺苷（cAMP）激活的氯/碳酸氢盐分泌，导致覆盖上皮细胞顶端表面的液体中碳酸氢盐浓度升高和pH值呈碱性。重要的是，嘌呤能刺激引发的黏蛋白释放需要基底外侧溶液中存在碳酸氢盐，并且在囊性纤维化患者来源的细胞中存在缺陷。总之，我们的结果表明，Th-2细胞因子可诱导多种离子通道和转运蛋白的表达和功能发生深刻变化，从而导致碳酸氢盐转运能力增强。这种变化是促进黏液释放和清除的重要机制。
