Mechanisms of Allergyp38 Mitogen-activated protein kinase–induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma☆,☆☆,★
Section snippets
Patients
Nine asthmatic subjects whose symptoms were controlled with ICSs (0.8 μg/d [95% CI, 0.2-1.3 μg/d], mean fluticasone equivalents), 19 steroid-dependent asthmatic subjects (poorly controlled on inhaled and oral steroids), and 6 healthy nonasthmatic subjects were studied. All subjects were matched in terms of age and atopic status (Table I).
Empty Cell Steroid-dependent subjects ICS subjects Healthy subjects No. of subjects 19 9 6 Age (y), mean (95% CI) 46 (40-52) 48
GR ligand binding of PBMCs
There was no significant difference in the cell profile of the PBMCs isolated from any subject group (data not shown). The ability of dexamethasone to bind to GR was decreased in the nucleus in subjects with steroid-depend-ent asthma. Steroid-dependent subjects (Kd, 39.8 ± 4.6 nmol/L) had a greater Kd compared with those with ICS-controlled asthma symptoms (Kd, 25 ± 0.9 nmol/L; P < .05) or healthy subjects (Kd, 6.79 ± 0.8 nmol/L; P < .001). In addition, there was a significant difference in Kd
Discussion
The ability of dexamethasone to bind to GR was decreased according to the degree of asthma severity. This difference was detected only in the nucleus and not in the cytoplasm, possibly reflecting an effect of a nuclear protein masking the GR ligand-binding site or in an altered conformation of the activated GR. This altered affinity of dexamethasone for GR may reflect either an intrinsic defect in the GR within these patients or may relate to changes in the receptor induced by the increased
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*These authors contributed equally to this work.
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Supported by the Wellcome Trust, the National Asthma Campaign, the Clinical Research Committee (Brompton Hospital), and Glaxo-Wellcome. E.I. is supported by the South African Pulmonology Society through a Grant from Boehringer Ingelheim (S.A.).
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Reprint requests: Ian M. Adcock, PhD, Thoracic Medicine, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK.