title: Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells.
abstract: A subset of asthma patients suffer from glucocorticoid (GC) insensitivity. T-helper cell type 17 cells have an emerging role in GC insensitivity, although the mechanisms are still poorly understood. We investigated whether interleukin (IL)-17A induces GC insensitivity in airway epithelium by studying its effects on responsiveness of tumour necrosis factor (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 a histone deacetylase (HDAC) activity assay. We demonstrated that IL-17A-induced IL-8 production is normally sensitive to GCs, while IL-17A pre-treatment significantly reduced the sensitivity of TNF-α-induced IL-8 production to budesonide. IL-17A activated the p38, extracellular signal-related kinase (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 have shown for the first time that IL-17A induces GC insensitivity in airway epithelium, which is probably 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.
authors.affiliation: Laboratory of Allergology and Pulmonary Diseases Dept of Pathology and Medical Biology GRIAC Research Institute University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Zijlstra
authors.forename: N H T
authors.initials: NH
authors.lastname: Ten Hacken
authors.forename: R F
authors.initials: RF
authors.lastname: Hoffmann
authors.forename: A J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.forename: I H
authors.initials: IH
authors.lastname: Heijink
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D002478:Cells, Cultured; D004351:Drug Resistance / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000276:immunology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D005938:Glucocorticoids; C508717:IL17A protein, human; D020381:Interleukin-17; D016209:Interleukin-8; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2