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Published ahead of print on December 30, 2005, doi:10.1164/rccm.200507-1046OC
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 607-616, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200507-1046OC

Original Article

Increased Glucocorticoid Receptor beta Alters Steroid Response in Glucocorticoid-insensitive Asthma

Elena Goleva*, Ling-bo Li*, P. Taylor Eves, Matthew J. Strand, Richard J. Martin and Donald Y. M. Leung

Department of Pediatrics, Department of Medicine, and Division of Biostatistics, Department of Medicine, National Jewish Medical and Research Center; and Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Donald Y. M. Leung, M.D., Ph.D., National Jewish Medical Research Center, 1400 Jackson Street, Room K926i, Denver, CO 80206. E-mail: leungd{at}njc.org

Rationale: Glucocorticoids (GCs) are highly effective in the treatment of asthma. However, some individuals have GC-insensitive asthma.

Objectives: To evaluate the functional response to steroids of bronchoalveolar lavage (BAL) cells from sites of airway inflammation from patients with GC-insensitive versus GC-sensitive asthma. As well, to attempt to define the functional role of glucocorticoid receptor (GCR)beta (a splicing variant, and dominant negative inhibitor of, the classic GCR{alpha}) in controlling GCR{alpha} nuclear translocation and transactivation at a molecular level.

Methods and Measurements: Fiberoptic bronchoscopy with collection of BAL fluid was performed on seven patients with GC-sensitive asthma and eight patients with GC-insensitive asthma. GCR{alpha} cellular shuttling in response to 10–6 M dexamethasone treatment and GCRbeta expression were analyzed in BAL cells by immunofluorescence staining. The effects of overexpression and silencing of GCRbeta mRNA on GCR{alpha} function were assessed.

Main Results: Significantly reduced nuclear translocation of GCR{alpha} in response to steroids was found in BAL cells from patients with GC-insensitive asthma. BAL macrophages from patients with GC-insensitive asthma had significantly increased levels of cytoplasmic and nuclear GCRbeta. It was demonstrated that GCR{alpha} nuclear translocation and its transactivation properties were proportionately reduced by level of viral transduction of the GCRbeta gene into the DO-11.10 cell line. RNA silencing of GCRbeta mRNA in human BAL macrophages from patients with GC-insensitive asthma resulted in enhanced dexamethasone-induced GCR{alpha} transactivation.

Conclusions: GC insensitivity is associated with loss of GCR{alpha} nuclear translocation in BAL cells and elevated GCRbeta, which may inhibit GCR{alpha} transactivation in response to steroids.

Key Words: asthma • bronchoalveolar lavage cells • glucocorticoid insensitivity • glucocorticoid receptor




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