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)-a-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-a-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. @ERSpublications Glucocorticoids enhance production of CCL20 by airway epithelial cells: a mechanism of inflammation in asthma?

Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium

“…They are also increased in many respiratory conditions. Unsurprisingly, striking variability of sputum neutrophil counts has been demonstrated in corticosteroid-treated asthma [2] and was also recorded by ZIJLSTRA et al [1]. The notion that corticosteroids cause neutrophilia by inhibiting apoptosis of these cells is flourishing in the literature.…”

“…This study nicely adds to the research demonstrating that corticosteroids not only inhibit the production of several inflammatory chemokines and cytokines, but also corticosteroids increase levels of certain regulatory proteins; these neutrophil-active proteins are potentially involved in inflammation or, indeed, in host defence. Hence, the data reported by ZIJLSTRA et al [1] may deserve attention beyond the focus given by the authors.…”

“…We read with interest the report by ZIJLSTRA et al [1] in which the effects of glucocorticoids possibly contributed to airway neutrophilia in asthma. This study nicely adds to the research demonstrating that corticosteroids not only inhibit the production of several inflammatory chemokines and cytokines, but also corticosteroids increase levels of certain regulatory proteins; these neutrophil-active proteins are potentially involved in inflammation or, indeed, in host defence.…”

“…Furthermore, UDDIN et al [5] excluded a role of corticosteroid treatment as a factor in pro-survival activity for airway neutrophils in severe asthma. Lack of support for apoptosis-related effects actually lends weight to the findings of ZIJLSTRA et al [1], suggesting that a chemoattractant such as CCL20 could be involved in corticosteroid-induced airway neutrophilia. corticosteroids significantly upregulated interleukin-8, interferon-γ-inducible protein 10 and monocyte chemotactic protein-2 in asthmatic bronchial walls.…”

“…It is so established that there is no longer any need to present supporting evidence [3]. ZIJLSTRA et al [1] do not discuss this aspect but their choice of reference regarding neutrophilic asthma is focussed on popular roles of apoptosis.…”