The Journal of Experimental Medicine
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Published online 30 August 2004 doi:10.1084/jem.20040416
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 5, 689-695
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*COPD (Chronic Obstructive Pulmonary Disease)
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*THEOPHYLLINE
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Brief Definitive Report

 Theophylline Restores Histone Deacetylase Activity and Steroid Responses in COPD Macrophages

Borja G. Cosio, Loukia Tsaprouni, Kazuhiro Ito, Elen Jazrawi, Ian M. Adcock, and Peter J. Barnes

Thoracic Medicine, National Heart and Lung Institute, Imperial College, London SW3 6LY, England, UK

Address correspondence to Peter J. Barnes, Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse St., London SW3 6LY, England, UK. Phone: 44-207-351-8174; Fax: 44-207-351-5675; email: p.j.barnes{at}imperial.ac.uk

Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells of cigarette smokers, and low concentrations of theophylline can increase HDAC activity. We measured the effect of theophylline on HDAC activity and inflammatory gene expression in alveolar macrophages (AM) from patients with COPD. AM from normal smokers showed a decrease in HDAC activity compared with normal control subjects, and this was further reduced in COPD patients (51% decrease, P < 0.01). COPD AMs also showed increased basal release of IL-8 and TNF-{alpha}, which was poorly suppressed by dexamethasone. Theophylline induced a sixfold increase in HDAC activity in COPD AM lysates and significantly enhanced dexamethasone suppression of induced IL-8 release, an effect that was blocked by the HDAC inhibitor trichostatin A. Therefore, theophylline might restore steroid responsiveness in COPD patients.

Key Words: histone deacetylase • theophylline • steroid resistance • COPD • interleukin-8


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