Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide.

Kelly, M. M. and King, E. M. and Rider, C. F. and Gwozd, C. and Holden, Neil S. and Eddleston, J. and Zuraw, B. and Leigh, R. and O'Byrne, P. M. and Newton, R. (2012) Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide. British Journal of Pharmacology, 165 (6). pp. 1737-1747. ISSN 0007-1188

Full content URL: http://dx.doi.org/10.1111/j.1476-5381.2011.01620.x

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Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide

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Abstract

BACKGROUND AND PURPOSE

Inhaled 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 APPROACH

Bronchial 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 RESULTS

Compared 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 IMPLICATIONS

Expression 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.

Keywords:Corticosteroid, GILZ, epithelial cells, Smooth muscle cells, Asthma
Subjects:B Subjects allied to Medicine > B210 Pharmacology
A Medicine and Dentistry > A990 Medicine and Dentistry not elsewhere classified
Divisions:College of Science > School of Life Sciences
ID Code:15117
Deposited On:22 Oct 2014 11:36

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