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

Abstract

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).

• Authors: Ling-Bo Li, Donald Y M Leung, Richard J Martin, Elena Goleva
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 182 Issue 7 Pg. 877-83 (Oct 01 2010) ISSN: 1535-4970 [Electronic] United States
• PMID: 20538962 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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