Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform.
BACKGROUND
Glucocorticoid-resistant bronchial asthma is characterized by failure of corticosteroids to suppress key asthma-relevant, cell-mediated inflammatory responses in the airways.


OBJECTIVE
The mechanism of this phenomenon is not clear but may involve aberrant expression of the beta-isoform of the glucocorticoid receptor.


METHODS
We have measured expression of the alpha- and beta-glucocorticoid receptor isoforms in tuberculin-driven cutaneous cell-mediated inflammatory lesions in people with asthma who are glucocorticoid sensitive and resistant after 9 days of therapy with oral prednisolone (40 mg/day) or matching placebo in a random order, crossover design.


RESULTS
After placebo therapy, the mean numbers of cells expressing glucocorticoid receptor alpha immunoreactivity in the lesions evoked in glucocorticoid-sensitive and -resistant patients with asthma were statistically equivalent. The numbers of cells expressing glucocorticoid receptor beta were significantly elevated in the patients who were glucocorticoid resistant, resulting in an 8-fold higher ratio of expression of glucocorticoid receptor alpha/glucocorticoid receptor beta in the patients who were glucocorticoid sensitive. Glucocorticoid receptor alpha/glucocorticoid receptors beta were colocalized to the same cells. Oral prednisolone therapy was associated with a significant decrease in the numbers of cells expressing glucocorticoid receptor alpha but not glucocorticoid receptor beta in the subjects who were glucocorticoid sensitive. No significant change was found in the numbers of cells expressing glucocorticoid receptor alpha and glucocorticoid receptor beta in the patients who were glucocorticoid resistant. Prednisolone therapy reduced the ratio of glucocorticoid receptor alpha/glucocorticoid receptor beta expression for the patients who were glucocorticoid sensitive to a level seen in the patients who were glucocorticoid resistant before therapy.


CONCLUSIONS
Because glucocorticoid receptor beta inhibits alpha-glucocorticoid receptor-mediated transactivation of target genes, the increased expression of glucocorticoid receptor beta in inflammatory cells might be a critical mechanism for conferring glucocorticoid resistance.
Sousa
A R
AR
Department of Respiratory Medicine and Allergy, King's College London, Guy's Hospital, London, UK.
Lane
S J
SJ
Cidlowski
J A
JA
Staynov
D Z
DZ
Lee
T H
TH
D000328:Adult; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count / Q000187:drug effects; D004351:Drug Resistance; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008264:Macrophages / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000494:pharmacology; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000097:blood; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000097:blood; D013194:Staining and Labeling; D013601:T-Lymphocytes / Q000737:chemistry
D005938:Glucocorticoids; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D011239:Prednisolone