Mechanisms of asthma and allergic inflammationDefective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients
Section snippets
Patients
Six glucocorticoid-sensitive subjects (SS; controlled on inhaled steroids), 11 glucocorticoid-dependent asthmatic subjects (SD; controlled only on oral steroids), 9 steroid-resistant asthmatic subjects who showed no response even to high doses of oral steroids (SR), and 10 normal nonasthmatic control subjects were studied (Table I). All subjects were matched for age, and no current smokers were included in the study. The SD (2.7 ± 2 pack years) and SR (0.1 ± 0.2 pack years) groups included some
Effect of dexamethasone on TNF-α–induced GM-CSF production in PBMCs
The basal levels of GM-CSF production from PBMCs (106 cells) from normal subjects and SS, SD, and SR patients were similar in all groups. GM-CSF release was enhanced by TNF-α (10 ng/mL) in all groups to a similar extent (normal, 124 ± 10; SS, 137 ± 25; SD, 164 ± 17; SR, 103 ± 9 pg/mL). Dexamethasone (10−6 mol/L) inhibited TNF-α–induced GM-CSF production in all subject groups according to the in vivo efficacy of glucocorticoids in each subject group. Dexamethasone produced a similar level of
Discussion
PBMCs from SD and SR patients had a reduced ability to suppress TNF-α–induced GM-CSF release compared with normal and SS subjects. In most SD and SR subjects, this failure to attenuate GM-CSF release was correlated with a reduced ability of GR to translocate to the nucleus and induce histone acetylation in response to dexamethasone. These subjects were also unable to repress TNF-α–induced histone acetylation (group 1). In addition, we have also identified a distinct subgroup within SD and SR
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Supported by the Wellcome Trust, the National Asthma Campaign, the Clinical Research Committee (Royal Brompton Hospital), and GlaxoSmithKline (United Kingdom).
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These authors contributed equally to this work.