Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium

G. Jan Zijlstra, Fatemeh Fattahi, Dennie Rozeveld, Marnix R. Jonker, Nathalie M. Kliphuis, Maarten van den Berge, Machteld N. Hylkema, Nick H. T. Hacken, ten, Antoon J. M. van Oosterhout, Irene H. Heijink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)

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 (TNE)-alpha-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-alpha-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.

Original languageEnglish
Pages (from-to)361-370
Number of pages10
JournalEuropean Respiratory Journal
Volume44
Issue number2
DOIs
Publication statusPublished - Aug-2014

Keywords

  • T(H)17 CELLS
  • TNF-ALPHA
  • ASTHMA
  • INFLAMMATION
  • EXPRESSION
  • RECEPTOR
  • RECRUITMENT
  • ACTIVATION
  • ADAM17
  • IL-17

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