Stimulation of Cytokine Expression in Human Airway Epithelial Cells by IL‐17A: Polarity of Receptor Distribution and Dependence on PI3 Kinase/NF‐κB Signaling Pathways

Abstract

The pro-inflammatory effects of IL-17A on airway epithelial cells have been recognized. In order to elucidate the signaling of IL-17A in the airway, primary human tracheobronchial epithelial cells (TBE) and HBE1 cell line were cultured under an air-liquid biphasic condition. Differential gene expression was determined by Affymetrix gene chips. We have observed gene induction of IL-19, GRO-α, -β, -γ, CXCL-5 and GCP-2 by IL-17A in addition to those in previous studies, such as HBD2, CCL20, and mucin genes, which were further confirmed by Q-PCR. Polarity of the treatment and anti-IL-17 receptor A (IL-17AR) antibody staining consistently showed the localization preference of IL-17AR is at the basal-lateral side of the epithelium. Inhibitor studies demonstrated that the gene induction is sensitive to the inhibition of PI3K and NF-κB activation. This is further supported by protein analysis, nuclear translocation and HBD-2 promoter analysis. However, PI3K inhibitor (LY294002) has no effects on NF-κB translocation, suggesting an additional PI3K-independent event is involved in coordinating the NF-κB-based transcriptional regulation. Based on these results, IL-17A basal-laterally acts through the IL-17 AR of the polarized airway epithelium to exert the activation of PI3 kinase signaling and NF-κB translocation to activate the expression of various cytokines.