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Updated: May 5, 2026
Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
Published on: September 21, 2011
Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid
M Kraft1, E Vianna, R J Martin
1Departments of Medicine and Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Background:
The mechanisms for heightened nocturnal inflammation in patients with nocturnal asthma (NA) are not well understood.
Objective:
We sought to determine the glucocorticoid receptor (GR) characteristics and steroid responsiveness in subjects with NA.
Methods:
Eleven subjects with NA, 12 subjects with nonnocturnal asthma (NNA), and 16 nonasthmatic control subjects underwent blood sampling at 4 pm and 4 am in a random order separated by 1 week. GR binding affinity was measured in PBMCs by using a [3H]-dexamethasone (DX) radioligand binding assay and Scatchard analysis. The capacity of hydrocortisone (HC) and DX to suppress proliferation of PBMCs stimulated with PHA was also determined.
Results:
The subjects with NA exhibited a significantly lower GR binding affinity at 4 am, detected by an elevated dissociation constant (Kd) of 22.2 +/- 1.6 nmol/L compared with Kd at 4 pm (10.9 +/- 0.7 nmol/L; P =.0001). The GR Kd of the NNA and control groups did not change significantly from 4 pm to 4 am. Within the NA group, there was also a significant inverse correlation between the absolute FEV1 at 4 am and the Kd at 4 am (r = -0.65, P =.04). PBMCs from subjects with NA exhibited less suppression of PBMC proliferation with HC and DX at 4 am compared with that at 4 pm (P =.0004 and.03 for HC and DX, respectively). There were no circadian changes in suppression of PBMC proliferation in either the NNA or control groups.
Conclusion:
GR binding affinity and steroid responsiveness exhibit a circadian variation in subjects with NA, with a reduced GR binding affinity and suppression of PBMC proliferation at 4 am that is not observed in normal subjects or asthmatic subjects without nocturnal exacerbation. These observations may contribute to nocturnal airway inflammation by inhibiting the antiinflammatory effects of glucocorticoids.
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