PT - JOURNAL ARTICLE AU - Jan Zijlstra AU - Dennie Rozeveld AU - Nick ten Hacken AU - Antoon van Oosterhout AU - Irene Heijink TI - Glucocorticoids enhance CCL20 release in bronchial epithelial cells in a metalloprotease-dependent manner DP - 2011 Sep 01 TA - European Respiratory Journal PG - p3096 VI - 38 IP - Suppl 55 4099 - http://erj.ersjournals.com/content/38/Suppl_55/p3096.short 4100 - http://erj.ersjournals.com/content/38/Suppl_55/p3096.full SO - Eur Respir J2011 Sep 01; 38 AB - Glucocorticoid (GC) insensitivity is a major clinical problem in the management of asthma. Although a potential role for Th17 cells has been described in GC insensitive asthma, it is still unknown why GCs are unable to efficiently suppress Th17-mediated inflammation. CCL20 acts as a potent chemoattractant for Th17 cells. To determine the effect of GCs on CCL20 secretion and to unravel the underlying regulatory mechanisms, we examined the effect of budesonide and fluticasone (10-7-10-10M) on TNF-α-induced CCL20 and IL-8 production (ELISA and qPCR) in 16HBE human bronchial epithelial cells and primary bronchial asthma epithelium. We used specific inhibitors for the ERK, p38, STAT3 and PI3K pathways, the GC-receptor (GR), protein synthesis and a general metalloprotease inhibitor.Surprisingly, we observed that GCs do not suppress, but enhance the release of CCL20 in by 16HBE cells, under conditions where IL-8 was efficiently suppressed. Importantly, GCs also induced a substantial increase in the TNF-α-induced release of CCL20 in asthma epithelium. Although the TNF-α-induced CCL20 release was dependent on the ERK, p38 and STAT3 pathways, the upregulation by GCs was not blocked by their inhibition. Furthermore, our data demonstrate that the effect of GC is mediated by GR activation, which is likely mediated at posttranslational level in a metalloprotease-dependent manner.Thus, we show for the first time that GCs enhance metalloprotease-dependent release of CCL20, which may constitute a novel mechanism of Th17-mediated GC insensitive neutrophilic airway inflammation in asthma and provide new opportunities for therapeutic intervention.