M M Kelly1, E M King1, C F Rider1, C Gwozd1, N S Holden1, J Eddleston1, B Zuraw1, R Leigh1, P M O'Byrne1, R Newton1. 1. Airways Inflammation Research Group, Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary, Calgary, AB, CanadaAllergy and Immunology Section, University of California, San Diego School of Medicine, La Jolla, CA, USAFirestone Institute for Respiratory Health, St. Joseph's Hospital and the Department of Medicine, McMaster University, Hamilton, ON, Canada.
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 inhaledbudesonide 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 inhaledbudesonide. 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.
RCT Entities:
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.
Authors: Margaret M Kelly; Richard Leigh; Sarah E Gilpin; Elaine Cheng; Gail E M Martin; Katherine Radford; Gerard Cox; Jack Gauldie Journal: Am J Respir Crit Care Med Date: 2006-05-25 Impact factor: 21.405
Authors: Joanna E Chivers; Wei Gong; Elizabeth M King; Joachim Seybold; Judith C Mak; Louise E Donnelly; Neil S Holden; Robert Newton Journal: Mol Pharmacol Date: 2006-09-20 Impact factor: 4.436
Authors: Marina Lasa; Sonya M Abraham; Christine Boucheron; Jeremy Saklatvala; Andrew R Clark Journal: Mol Cell Biol Date: 2002-11 Impact factor: 4.272
Authors: Sonya M Abraham; Toby Lawrence; Anna Kleiman; Paul Warden; Mino Medghalchi; Jan Tuckermann; Jeremy Saklatvala; Andrew R Clark Journal: J Exp Med Date: 2006-07-31 Impact factor: 14.307
Authors: Sunita Sharma; Alvin T Kho; Divya Chhabra; Weiliang Qiu; Roger Gaedigk; Carrie A Vyhlidal; J Steven Leeder; Albino Barraza-Villarreal; Stephanie J London; Frank Gilliland; Benjamin A Raby; Scott T Weiss; Kelan G Tantisira Journal: Am J Respir Cell Mol Biol Date: 2015-05 Impact factor: 6.914