Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma

Am J Respir Crit Care Med. 2010 Oct 1;182(7):877-83. doi: 10.1164/rccm.201001-0015OC. Epub 2010 Jun 10.


Rationale: Cross-talk between glucocorticoid receptors and histone deacetylases (HDACs) under steroid-insensitive conditions has not been explored.

Objectives: To evaluate expression and interaction of HDACs with glucocorticoid receptor isoforms in bronchoalveolar lavage and peripheral blood mononuclear cells from steroid-resistant versus steroid-sensitive patients with asthma.

Methods: Expression of HDACs 1 through 11 was measured by real-time polymerase chain reaction in primary cells and in the DO11.10 cell line, designed to overexpress glucocorticoid receptor β. Glucocorticoid receptor β expression was inhibited in bronchoalveolar lavage cells by small interfering RNA. Human HDAC2 promoter fragments were cloned into a luciferase reporter vector, and transiently transfected with glucocorticoid receptor α- and β-encoding plasmids into the cells. Luciferase activity was then assayed in response to glucocorticoids.

Measurements and main results: Levels of HDAC2 mRNA, but not other histone deacetylases, were significantly decreased in bronchoalveolar lavage cells but not in peripheral blood mononuclear cells from steroid-resistant patients with asthma. Overexpression of glucocorticoid receptor β in DO11.10 cells selectively reduced HDAC2 mRNA and protein levels. Silencing of glucocorticoid receptor β in bronchoalveolar lavage cells from patients with asthma significantly increased HDAC2 mRNA. Luciferase activity assays with HDAC2 promoter reporter constructs identified two glucocorticoid-inducible regions in the HDAC2 promoter. Promoter activity was increased more than fourfold in dexamethasone-treated cells cotransfected with glucocorticoid receptor α. Cotransfection of glucocorticoid receptor β abolished this effect in a dose-dependent manner.

Conclusions: Glucocorticoid receptor β controls expression of histone deacetylase 2 by inhibiting glucocorticoid response elements in its promoter. This highlights a novel mechanism by which glucocorticoid receptor β promotes steroid insensitivity (Li et al.: J Allergy Clin Immunol 2009;123:S146; and Li et al.: J Allergy Clin Immunol 2010;125:AB104).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Asthma / drug therapy
  • Asthma / genetics
  • Asthma / physiopathology*
  • Bronchoalveolar Lavage Fluid
  • Drug Resistance / genetics*
  • Gene Expression Regulation*
  • Glucocorticoids / pharmacology*
  • Histone Deacetylase 2 / antagonists & inhibitors*
  • Histone Deacetylase 2 / genetics
  • Humans
  • Leukocytes, Mononuclear
  • Promoter Regions, Genetic
  • Receptor Cross-Talk*
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Response Elements / genetics*


  • Glucocorticoids
  • Receptors, Glucocorticoid
  • glucocorticoid receptor beta
  • Histone Deacetylase 2