Upregulation of glucocorticoid receptor beta (GR beta) has been implicated in steroid resistance in severe asthma in previous studies with some conflicting results. GR beta has been proposed as a dominant negative isoform of glucocorticoid receptor alpha (GR alpha). It has been suggested that GR beta can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2).
Epigenetic determinants activate or silence genes through alterations in DNA, histone methylation and acetylation.
DNA associates with histone proteins to form chromatin. Image source: Wikipedia, GNU Free Documentation License.
This bronchoscopic study from two UK centres found that protein and RNA expression for GR alpha, GR beta, and HDAC2 did not differ between patients with different asthma severity and controls. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers.
The authors concluded that HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GR beta and reduced HDAC expression as the mechanism of steroid resistance in severe asthma. Conflicting literature findings may be explained by cross-reactivity of commercially-available antibody tests.
Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma. Thorax 2012;67:392-398 doi:10.1136/thoraxjnl-2011-200760,