In many chronic inflammatory disorders, glucocorticoid (GC) insensitivity is a challenging clinical problem associated with life-threatening disease progression. The molecular basis of GC insensitivity, however, is unknown. Alternative splicing of the GC receptor (R) pre–messenger RNA generates a second GCR, termed GCR-β, which does not bind GCs but antagonizes the transactivating activity of the classic GCR, termed GCR-α. In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR-β–immunoreactive cells in peripheral blood than GC-sensitive asthmatics or normal controls. Furthermore, we show that patients with GC-insensitive asthma have cytokine-induced abnormalities in the DNA binding capability of the GCR. These abnormalities can be reproduced by transfection of cell lines with the GCR-β gene resulting in significant reduction of their GCR-α DNA binding capacity. We conclude that increased expression of GCR-β is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.
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3 November 1997
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November 03 1997
Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor β
Donald Y.M. Leung,
Donald Y.M. Leung
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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Qutayba Hamid,
Qutayba Hamid
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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Alessandra Vottero,
Alessandra Vottero
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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Stanley J. Szefler,
Stanley J. Szefler
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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Wendy Surs,
Wendy Surs
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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Eleanor Minshall,
Eleanor Minshall
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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George P. Chrousos,
George P. Chrousos
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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Dwight J. Klemm
Dwight J. Klemm
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
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Donald Y.M. Leung
,
Qutayba Hamid
,
Alessandra Vottero
,
Stanley J. Szefler
,
Wendy Surs
,
Eleanor Minshall
,
George P. Chrousos
,
Dwight J. Klemm
From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the ‡Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the §Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the §Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland
Address Correspondence to Dr. Donald Y.M. Leung, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Phone: 303-398-1379; FAX: 303-270-2182; E-mail: [email protected]
1
Abbreviations used in this paper: EMSA, electromobility shift assay; FEV1, forced expiratory volume in one second; GC, glucocorticoid; GRE, glucorticoid response element; mRNA, messenger RNA.
Received:
May 28 1997
Revision Received:
August 20 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (9): 1567–1574.
Article history
Received:
May 28 1997
Revision Received:
August 20 1997
Citation
Donald Y.M. Leung, Qutayba Hamid, Alessandra Vottero, Stanley J. Szefler, Wendy Surs, Eleanor Minshall, George P. Chrousos, Dwight J. Klemm; Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor β . J Exp Med 3 November 1997; 186 (9): 1567–1574. doi: https://doi.org/10.1084/jem.186.9.1567
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