Expression and Activity of Histone Deacetylases in Human Asthmatic Airways

Abstract

Asthma is a chronic inflammatory disease that is characterized by increased expression of multiple inflammatory genes. Chromatin modification plays a critical role in the regulation of these genes. Acetyaltion of histones by histone acetyltransferases (HATs) is associated with increased gene transcription, whereas hypocetylation induced by histone deacetylases (HDACs) is associated with suppression of gene expression. We have examined the expression and activity of HATs and HDACs in bronchial biopsies from normal subjects and subjects with asthma. There was no difference in the site of HDAC1-HDAC6 expression between normal subjects and subjects with asthma, but subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression, as measured by Western blotting. In contrast, subjects with asthma treated with inhaled steroids were found to have greater HDAC activity than untreated subjects with asthma, although still lower than control subjects. In contrast, although there was no change in the site of HAT (CREB binding protein and p300/CREB binding protein-associated factor) expression, HAT activity was increased in subjects with asthma. HAT activity was reduced to control levels in subjects with asthma treated with inhaled steroids. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids.

Relative Corticosteroid Insensitivity of Peripheral Blood Mononuclear Cells in Severe Asthma

“…It has therefore been proposed that the balance of histone acetylation and of histone deacetylation may determine the inflammatory state. Glucocorticoids have been shown to suppress inflammatory gene expression, and this effect may involve the recruitment of HDACs to the transcriptional machinery complex by the activated glucocorticoid receptor (20,21).…”

Corticosteroid effects on cell signalling

“…There is evidence that the different HDACs target different patterns of acetylation [17]. In biopsy specimens from patients with asthma, there is an increase in HAT and a reduction in HDAC activity, thereby favouring increased inflammatory gene expression [18]. Against this background, it is now possible to better understand why corticosteroids are so effective in suppressing this complex inflammatory process that involves the increased expression of multiple inflammatory proteins.…”

How Do Corticosteroids Work in Asthma?

“…The acetylation of histone that is associated with increased expression of inflammatory genes is counteracted by the activity of HDACs (more than 12 that are associated with gene suppression have been characterized [10]). In biopsy samples from patients with asthma, HAT activity is increased and HDAC activity is decreased, thus favoring increased inflammatory gene expression (11). Improved understanding of the molecular basis of asthma has helped to explain how corticosteroids are so effective in suppressing this complex inflammation that involves many cells, mediators, and inflammatory effects.…”