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Published ahead of print on April 15, 2004, doi:10.1164/rccm.200305-659OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 2, July 2004, 141-147

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Submitted on May 15, 2003
Accepted on April 9, 2004

Histone Acetylase and Deacetylase Activity in Alveolar Macrophages and Blood Mononocytes in Asthma

Borja G Cosio1, Buphinder Mann1, Kazuhiro Ito1, Elen Jazrawi1, Peter J Barnes1, K Fan Chung1, and Ian M Adcock1*

1 Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College Faculty of Medicine, London, United Kingdom

* To whom correspondence should be addressed. E-mail: ian.adcock{at}ic.ac.uk.

Histone acetylation status is a key factor in the regulation of inflammatory gene transcription. We investigated the activity of histone acetylases (HAT) and deacetylases (HDAC) in alveolar macrophages (AM) and peripheral blood mononuclear cells (PBMCs) from asthmatic subjects and the effect of glucocorticoids. Bronchoalveolar lavage was performed in 10 patients with intermittent asthma, eight with persistent asthma and 10 healthy controls. PBMCs and granulocytes were isolated from 6 patients with mild and severe asthma, before and after a 7 day-course of prednisolone (30 mg daily). AM were isolated for HDAC assay or incubated with dexamethasone (1µM). HAT activity was increased (1.43±0.1 vs. 1.01±0.1 SU/10µg, p<0.05) and HDAC activity was reduced (3031±243 vs. 5004±164 AFU/10µg, p<0.001) in AM from asthmatics compared to control. Dexamethasone suppressed LPS-induced GM-CSF, TNFa and IL-8 release by 83±1%, 51±7% and 20±9% (p<0.001) respectively. This suppression was mimicked by nuclear factor-kB inhibition and IL-8 release was further reduced by the HDAC enhancer, theophylline (37±6%). Prednisolone increased HDAC activity in PBMCs from mild asthmatics. The increased inflammatory response in asthma may be due to reduced HDAC and enhanced HAT activity. Glucocorticoids and theophylline may down-regulate the inflammatory response by modulating HAT and HDAC activity and NF-kB activation.
Key words: inflammation, chromatin remodelling, theophylline, glucocorticoids, asthma




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