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J. Exp. Med.,
Volume 186, Number 9, November 3, 1997 1567-1574
By
From the * Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and
Research Center, and the 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- 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
, which does not bind GCs but antagonizes
the transactivating activity of the classic GCR, termed GCR-
. In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR--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- gene resulting in significant reduction of their GCR-
DNA binding capacity. We conclude that increased expression of GCR- is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.
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