Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform

Department of Respiratory Medicine and Allergy, King's College London, Guy's Hospital, London, UK.
Journal of Allergy and Clinical Immunology (Impact Factor: 11.25). 06/2000; 105(5):943-50. DOI: 10.1067/mai.2000.106486
Source: PubMed

ABSTRACT Glucocorticoid-resistant bronchial asthma is characterized by failure of corticosteroids to suppress key asthma-relevant, cell-mediated inflammatory responses in the airways.
The mechanism of this phenomenon is not clear but may involve aberrant expression of the beta-isoform of the glucocorticoid receptor.
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.
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.
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.

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    • "GRβ has been suggested to be upregulated in the steroid resistant asthmatics, and to be the most abundant GR isoform in neutrophils. GRβ was more highly expressed in glucocorticoid resistant asthmatics (Leung et al., 1997; Hamid et al., 1999; Sousa et al., 2000), although this is not a universal observation in glucocorticoid dependent (Gagliardo "
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    • "The precise molecular mechanisms underlying glucocorticoid sensitivity remain to be elucidated. However , it has been suggested that alternative splicing of the glucocorticoid receptor (GCR) in infiltrating T cells (Leung et al. 1998) and bronchial epithelial cells (Sousa et al. 2000) at the mRNA level generates GCR. The latter differs from GCR in the carboxy-terminal portion of the molecule and does not bind glucocorticoids and thus antagonises the transactivating ability of GCR. "
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