PT  - JOURNAL ARTICLE
AU  - G. Jan Zijlstra
AU  - N.H.T. ten Hacken
AU  - R.F. Hoffmann
AU  - A.J.M. van Oosterhout
AU  - I.H. Heijink
TI  - IL-17A induces glucocorticoid insensitivity in human bronchial epithelial cells
AID  - 10.1183/09031936.00017911
DP  - 2011 Jan 01
TA  - European Respiratory Journal
PG  - erj00179-2011
4099  - http://erj.ersjournals.com/content/early/2011/08/04/09031936.00017911.short
4100  - http://erj.ersjournals.com/content/early/2011/08/04/09031936.00017911.full
AB  - A subset of asthma patients suffers from glucocorticoid (GC)-insensitivity. Th17 cells have an emerging role in GC-insensitivity, although the mechanisms are still poorly understood.We investigated whether IL-17A induces GC-insensitivity in airway epithelium by studying its effects on responsiveness of TNF-α-induced IL-8 production to budesonide in human bronchial epithelial 16HBE cells. We unravelled the underlying mechanism by the use of specific pathway inhibitors, reporter- and overexpression constructs and an HDAC activity assay.We demonstrate that IL-17A-induced IL-8 production is normally sensitive to GCs, while IL-17A pre-treatment significantly reduces the sensitivity of TNF-α-induced IL-8 production to budesonide. IL-17A activated the p38, ERK and phosphoinositide-3-kinase (PI3K) pathways, and the latter appeared to be involved in IL-17A-induced GC-insensitivity. Furthermore, IL-17A reduced HDAC activity, and overexpression of HDAC2 reversed IL-17A-induced GC-insensitivity. In contrast, IL-17A did not affect budesonide-induced transcriptional activity of the GC receptor, suggesting that IL-17A does not impair the actions of the ligated GC receptor.In conclusion, we show for the first time that IL-17A induces GC-insensitivity in airway epithelium, which is likely mediated by PI3K activation and subsequent reduction of HDAC2 activity. Thus, blockade of IL-17A or downstream signalling molecule PI3K may offer new strategies for therapeutic intervention in GC-insensitive asthma.