Abstract
The epithelium plays an active role in the response to inhaled pathogens in part by responding to signals from the immune system. Epithelial responses may include changes in chemokine expression, increased mucin production and antimicrobial peptide secretion, and changes in ion transport. We previously demonstrated that interleukin-17A (IL-17A), which is critical for lung host defense against extracellular bacteria, significantly raised airway surface pH in vitro, a finding that is common to a number of inflammatory diseases. Using microarray analysis of normal human bronchial epithelial (HBE) cells treated with IL-17A, we identified the electroneutral chloride-bicarbonate exchanger Pendrin (SLC26A4) as a potential mediator of this effect. These data were verified by real-time, quantitative PCR that demonstrated a time-dependent increase in Pendrin mRNA expression in HBE cells treated with IL-17A up to 48 h. Using immunoblotting and immunofluorescence, we confirmed that Pendrin protein expression is increased in IL-17 treated HBE cells and that it is primarily localized to the mucosal surface of the cells. Functional studies using live-cell fluorescence to measure intracellular pH demonstrated that IL-17A induced chloride-bicarbonate exchange in HBE cells that was not present in the absence of IL-17A. Furthermore, HBE cells treated with short interfering RNA against Pendrin showed substantially reduced chloride-bicarbonate exchange. These data suggest that Pendrin is part of IL-17A-dependent epithelial changes and that Pendrin may therefore be a therapeutic target in IL-17A-dependent lung disease.
Highlights
IL-17A plays a central role in multiple facets of the immune response of the lung
Our microarray data strongly suggested that IL-17A increased Pendrin expression in normal human bronchial epithelial (HBE) cells
These data confirmed that IL-17A significantly increased Pendrin mRNA expression (Figure 1a) in a time-dependent manner, with increases appearing by 6 h and maximal at 48 h, the longest time point measured (Figure 1b)
Summary
IL-17A plays a central role in multiple facets of the immune response of the lung. Its activity is critical for host defense against extracellular bacteria including Haemophilus influenzae [1,2] and Staphylococcus aureus [3,4,5]. In patients with Hyper-IgE syndrome, who lack ThIL-17 cells, Sa skin and lung infections are common [5]. Loss of ThIL-17-mediated immunity after influenza infection predisposes to Sa pneumonia [6]. ThIL-17 cells, the main producers of IL-17A, are found in airways submucosa early in the course of cystic fibrosis (CF) [7], and IL-17A levels are increased in sputum during pulmonary exacerbations of CF and return to normal only after treatment [1,8]. IL-17A is thought to contribute to the neutrophilic airways inflammation seen in severe asthmatics [9]
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