title: Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium.
abstract: Th17-mediated neutrophilic airway inflammation has been implicated in decreased response to glucocorticoids in asthma. We aimed to investigate the effect of glucocorticoids on the airway epithelial release of the neutrophilic and Th17-cell chemoattractant CCL20. We studied CCL20 and CXCL8 sputum levels in asthmatic subjects using inhaled glucocorticoids or not, and the effect of budesonide on CCL20 and CXCL8 production in primary bronchial epithelial cells. The mechanism behind the effect of budesonide-induced CCL20 production was studied in 16HBE14o- cells using inhibitors for the glucocorticoid receptor, intracellular pathways and metalloproteases. We observed higher levels of CCL20, but not CXCL8, in the sputum of asthmatics who used inhaled glucocorticoids. CCL20 levels correlated with inhaled glucocorticoid dose and sputum neutrophils. Budesonide increased tumour necrosis factor (TNF)-α-induced CCL20 by primary bronchial epithelium, while CXCL8 was suppressed. In 16HBE14o- cells, similar effects were observed at the CCL20 protein and mRNA levels, indicating transcriptional regulation. Although TNF-α-induced CCL20 release was dependent on the ERK, p38 and STAT3 pathways, the increase by budesonide was not. Inhibition of glucocorticoid receptor or ADAM17 abrogated the budesonide-induced increase in CCL20 levels. We show that glucocorticoids enhance CCL20 production by bronchial epithelium, which may constitute a novel mechanism in Th17-mediated glucocorticoid-insensitive inflammation in asthma.
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen University of Groningen, University Medical Center Groningen, Dept of Pulmonology, Groningen.
authors.forename: G Jan
authors.initials: GJ
authors.lastname: Zijlstra
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen University of Groningen, University Medical Center Groningen, Dept of Pathology, Laboratory of Immunopathology, Groningen, The Netherlands.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Fattahi
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen.
authors.forename: Dennie
authors.initials: D
authors.lastname: Rozeveld
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen.
authors.forename: Marnix R
authors.initials: MR
authors.lastname: Jonker
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Kliphuis
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen University of Groningen, University Medical Center Groningen, Dept of Pulmonology, Groningen.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen University of Groningen, University Medical Center Groningen, Dept of Pathology, Laboratory of Immunopathology, Groningen, The Netherlands.
authors.forename: Machteld N
authors.initials: MN
authors.lastname: Hylkema
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen University of Groningen, University Medical Center Groningen, Dept of Pulmonology, Groningen.
authors.forename: Nick H T
authors.initials: NH
authors.lastname: ten Hacken
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen.
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen University of Groningen, University Medical Center Groningen, GRIAC research Institute, Groningen h.i.heijink@umcg.nl.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D001249:Asthma / Q000378:metabolism*; D019819:Budesonide / Q000627:therapeutic use; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects; D004848:Epithelium / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013183:Sputum / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D054418:Chemokine CCL20; D005938:Glucocorticoids; D016209:Interleukin-8; D011965:Receptors, Glucocorticoid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D019819:Budesonide; D048049:Extracellular Signal-Regulated MAP Kinases; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human