BACKGROUND AND PURPOSEInhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma.
EXPERIMENTAL APPROACHBronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual-specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis.
KEY RESULTSCompared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide-treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects.
CONCLUSIONS AND IMPLICATIONSExpression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy.
AbbreviationsAP-1, activator protein 1; ASM, airway smooth muscle; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; FKBP51, FK506-binding protein 51; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GILZ, glucocorticoidinduced leucine zipper; GR, glucocorticoid receptor; GRE, glucocorticoid response element; HBE, human bronchial epithelial; ICS, inhaled corticosteroid; MKP, MAPK phosphatase; RT, reverse transcriptase BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 British Journal of Pharmacology (2012)
IntroductionIn asthma, inhaled corticosteroids (ICS), also called glucocorticoids, are highly effective at reducing inflammation and improving patient outcomes (Barnes, 2006), and ICS remain the cornerstone of pharmacological therapy (Bateman et al., 2008). ICS attenuate airway eosinophil numbers, reduce asthma exacerbations and mortality and lead to improvements in lung function and health-related quality of life (Suissa et al., 2000;Pauwels et al., 2003;Kelly et al., 2006b;Busse et al., 2008;Newton et al....