Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta

• Published in: The Journal of experimental medicine Vol. 186; no. 9; pp. 1567 - 1574
• Main Authors: Leung, D Y, Hamid, Q, Vottero, A, Szefler, S J, Surs, W, Minshall, E, Chrousos, G P, Klemm, D J
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 03-11-1997
• Subjects: Asthma - drug therapy; Asthma - metabolism; Cell Line; Cells, Cultured; DNA-Binding Proteins - drug effects; DNA-Binding Proteins - genetics; Drug Resistance; Electrophoresis, Polyacrylamide Gel; Glucocorticoids - antagonists & inhibitors; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Humans; Interleukin-2 - pharmacology; Interleukin-4 - pharmacology; Leukocytes, Mononuclear - metabolism; Receptors, Glucocorticoid - analysis; Receptors, Glucocorticoid - biosynthesis; Receptors, Glucocorticoid - genetics
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.186.9.1567

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.