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J. Exp. Med., Volume 186, Number 9, November 3, 1997 1567-1574

Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor beta  

By Donald Y.M. Leung,* Qutayba Hamid,Dagger Alessandra Vottero,§ Stanley J. Szefler,* Wendy Surs,* Eleanor Minshall,§ George P. Chrousos,§ and Dwight J. Klemm*

From the * Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the Dagger  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

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-beta , which does not bind GCs but antagonizes the transactivating activity of the classic GCR, termed GCR-alpha . In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR-beta -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-beta gene resulting in significant reduction of their GCR-alpha DNA binding capacity. We conclude that increased expression of GCR-beta is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.


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