Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta.
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.
Leung
D Y
DY
Division of Allergy-Immunology, National Jewish Medical and Research Center, Denver, CO 80206, USA. leungd@njc.org
Hamid
Q
Q
Vottero
A
A
Szefler
S J
SJ
Surs
W
W
Minshall
E
E
Chrousos
G P
GP
Klemm
D J
DJ
D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics; D004351:Drug Resistance; D004591:Electrophoresis, Polyacrylamide Gel; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D007376:Interleukin-2; D011965:Receptors, Glucocorticoid; D015847:Interleukin-4