Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma

作者：Claire Ann Butler, Stephen McQuaid, Clifford C. Taggart, Sinéad Weldon, Richard Carter, Grzegorz Skibiński, Timothy J. Warke, David F. Choy, Lorcan P. McGarvey, Peter Bradding, Joe R Arron, Liam Gabriel Heaney · 发表于：Thorax · 年份：2011 · DOI：10.1136/thoraxjnl-2011-200760 · 被引用次数：70 · 研究领域：Asthma and respiratory diseases、Histone Deacetylase Inhibitors Research、Estrogen and related hormone effects

RATIONALE: Upregulation of glucocorticoid receptor β (GRβ) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRβ has been proposed as a dominant negative isoform of glucocorticoid receptor α (GRα) but it has also been suggested that GRβ can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway. OBJECTIVES: To examine GRβ, GRα, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers. METHODS: Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRβ antibody. MEASUREMENTS AND MAIN RESULTS: Protein and mRNA expression for GRα and HDAC2 did not differ between groups. GRβ mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRβ antibody detected an additional 'cross-reacting' protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers. CONCLUSIONS: GRβ mRNA is expressed at low levels in a minority of patients with...