TY - JOUR T1 - IL-17A induces glucocorticoid insensitivity in airway epithelial cells JF - European Respiratory Journal JO - Eur Respir J VL - 38 IS - Suppl 55 SP - 1447 AU - Jan Zijlstra AU - Nick ten Hacken AU - Roland Hoffmann AU - Antoon van Oosterhout AU - Irene Heijink Y1 - 2011/09/01 UR - http://erj.ersjournals.com/content/38/Suppl_55/1447.abstract N2 - Glucocorticoids (GC) are the cornerstone of asthma treatment. However, a subset of asthma patients is insensitive, which is a problem in the management of asthma. Previous studies suggest that GC-insensitivity is associated with Th17 cells. Th17 cells act by producing inflammatory cytokines, including IL-17A. We aimed to assess whether IL-17A reduces GC sensitivity in airway epithelial cells and to elucidate the underlying mechanism.We investigated the effect of IL-17A on the suppressive effect of budesonide (BUD) (10-10-10-9M) on TNF-α-induced IL-8 secretion and on Histone Deacetylase (HDAC) activity in the human bronchial epithelial cell line 16HBE with/without specific inhibitors for the ERK, p38 and PI3K pathways and upon overexpression of HDAC2.We observed that IL-17A-induced IL-8 secretion is normally sensitive to GC in 16HBE, in contrast pre-treatment with IL-17A (2h) significantly reduces the sensitivity of TNF-α-induced IL-8 secretion to BUD. Immunodetection revealed that IL-17A activates the p38, ERK and PI3K pathways, but only inhibition of PI3K signaling reversed this GC-insensitivity. Our data suggest that IL-17A-induced GC-insensitivity is mediated by a reduction in HDAC2 activity, as IL-17A reduced HDAC activity, while overexpression of HDAC2 reversed IL-17A-induced GC-insensitivity. In contrast, IL-17A did not affect BUD-induced transcriptional activity, suggesting that IL-17A does not impair translocation of the ligated GC receptor.In conclusion, we show that IL-17A induces GC-insensitivity in bronchial epithelium which likely involves PI3K-dependent reduction in HDAC2 activity. IL-17A-induced PI3K signaling may thus serve as a new target for therapeutic intervention in GC-insensitive asthma. ER -