help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on December 30, 2005, doi:10.1164/rccm.200507-1046OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200507-1046OCv1
173/6/607    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goleva, E.
Right arrow Articles by Leung, D. Y. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goleva, E.
Right arrow Articles by Leung, D. Y. M.
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




This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
J. A. Marwick, G. Caramori, C. S. Stevenson, P. Casolari, E. Jazrawi, P. J. Barnes, K. Ito, I. M. Adcock, P. A. Kirkham, and A. Papi
Inhibition of PI3K{delta} Restores Glucocorticoid Function in Smoking-induced Airway Inflammation in Mice
Am. J. Respir. Crit. Care Med., April 1, 2009; 179(7): 542 - 548.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
E. Goleva, L.-b. Li, and D. Y. M. Leung
IFN-{gamma} Reverses IL-2- and IL-4-Mediated T-Cell Steroid Resistance
Am. J. Respir. Cell Mol. Biol., February 1, 2009; 40(2): 223 - 230.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. C. Chung, L. Shimmin, S. Natarajan, C. L. Hanis, E. Boerwinkle, and J. E. Hixson
Glucocorticoid Receptor Gene Variant in the 3' Untranslated Region Is Associated with Multiple Measures of Blood Pressure
J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 268 - 276.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
A. S. Tait, C. L. Butts, and E. M. Sternberg
The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease
J. Leukoc. Biol., October 1, 2008; 84(4): 924 - 931.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
E. R. Sutherland, E. Goleva, M. Strand, D. A. Beuther, and D. Y. M. Leung
Body Mass and Glucocorticoid Response in Asthma
Am. J. Respir. Crit. Care Med., October 1, 2008; 178(7): 682 - 687.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
I. M. Adcock and P. J. Barnes
Molecular Mechanisms of Corticosteroid Resistance
Chest, August 1, 2008; 134(2): 394 - 401.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. J. M. Schaaf, D. Champagne, I. H. C. van Laanen, D. C. W. A. van Wijk, A. H. Meijer, O. C. Meijer, H. P. Spaink, and M. K. Richardson
Discovery of a Functional Glucocorticoid Receptor {beta}-Isoform in Zebrafish
Endocrinology, April 1, 2008; 149(4): 1591 - 1599.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
L.-b. Li, D. Y. M. Leung, M. J. Strand, and E. Goleva
ATF2 impairs glucocorticoid receptor mediated transactivation in human CD8+ T cells
Blood, September 1, 2007; 110(5): 1570 - 1577.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
W. C. Moore and S. P. Peters
Update in Asthma 2006
Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 649 - 654.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. Jaradat, C. Stapleton, S. L. Tilley, D. Dixon, C. J. Erikson, J. G. McCaskill, H. S. Kang, M. Angers, G. Liao, J. Collins, et al.
Modulatory Role for Retinoid-related Orphan Receptor {alpha} in Allergen-induced Lung Inflammation
Am. J. Respir. Crit. Care Med., December 15, 2006; 174(12): 1299 - 1309.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
T. Tao, J. Lan, G. L. Lukacs, R. J. G. Hache, and F. Kaplan
Importin 13 Regulates Nuclear Import of the Glucocorticoid Receptor in Airway Epithelial Cells
Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 668 - 680.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. Hew, P. Bhavsar, A. Torrego, S. Meah, N. Khorasani, P. J. Barnes, I. Adcock, K. Fan Chung, and for the National Heart Lung and Blood Institute's
Relative Corticosteroid Insensitivity of Peripheral Blood Mononuclear Cells in Severe Asthma
Am. J. Respir. Crit. Care Med., July 15, 2006; 174(2): 134 - 141.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2006 American Thoracic Society 		  SOTA, FL