Abstract
The 3-gene airway epithelial gene signature of POSTN, CLCA1 and SERPINB2 has been proposed as a tool to classify asthma into T h 2-high and T h 2-low phenotypes. Clinical studies with macrolide antibiotics in asthma have shown promising results in certain asthma phenotypes, and macrolides are known to have anti-inflammatory and immune-modulatory properties in addition to being antimicrobial. Therefore, the aim of this study was to investigate the effect of the macrolide azithromycin (AZM) on IL-13-induced POSTN, CLCA1 and SERPINB2 expression in cultured primary human bronchial epithelial cells (PBEC). Additionally, we also investigated the effect of AZM on FOXA2, SPDEF and MUC5AC, important components of goblet cell metaplasia. PBEC cultured at an air liquid interface were exposed to 5 ng/ml IL-13 with or without AZM during 2 weeks. After exposure, FOXA2, SPDEF, MUC5AC, POSTN, CLCA1 and SERPINB2 expression was analysed using quantitative PCR, western blot or immunofluorescence. Exposure to IL-13 alone reduced FOXA2 expression and increased MUC5AC, SPDEF, POSTN, CLCA1 and SERPINB2 expression. AZM further increased IL-13-induced POSTN expression, whereas AZM reduced IL-13-induced MUC5AC, CLCA1 and SERPINB2 expression. AZM did not affect SPDEF expression. Additionally, IL-13 induced nuclear exclusion of FOXA2 which was partially prevented by AZM treatment. These results suggest that AZM controls POSTN, CLCA1 and SERPINB2 expression by affecting separate pathways. Additionally, AZM appears to decrease IL-13 induced MUC5AC expression by reducing CLCA1 expression and by redistribution of the inhibitory transcription factor FOXA2 within epithelial cells.
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