Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages.
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.
Cosio
Borja G
BG
Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse St., London SW3 6LY, England, UK.
Tsaprouni
Loukia
L
Ito
Kazuhiro
K
Jazrawi
Elen
E
Adcock
Ian M
IM
Barnes
Peter J
PJ
D000368:Aged; D015153:Blotting, Western; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D012907:Smoking; D013256:Steroids / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
D001993:Bronchodilator Agents; D006877:Hydroxamic Acids; D016209:Interleukin-8; D008070:Lipopolysaccharides; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha; C012589:trichostatin A; D013806:Theophylline; D006655:Histone Deacetylases; D005978:Glutathione