Original articles: Asthma, rhinitis, other respiratory diseases
Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform,☆☆

https://doi.org/10.1067/mai.2000.106486Get rights and content

Abstract

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 β-isoform of the glucocorticoid receptor. Methods: We have measured expression of the α- and β-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 α immunoreactivity in the lesions evoked in glucocorticoid-sensitive and -resistant patients with asthma were statistically equivalent. The numbers of cells expressing glucocorticoid receptor β were significantly elevated in the patients who were glucocorticoid resistant, resulting in an 8-fold higher ratio of expression of glucocorticoid receptor α/glucocorticoid receptor β in the patients who were glucocorticoid sensitive. Glucocorticoid receptor α/glucocorticoid receptors β were colocalized to the same cells. Oral prednisolone therapy was associated with a significant decrease in the numbers of cells expressing glucocorticoid receptor α but not glucocorticoid receptor β in the subjects who were glucocorticoid sensitive. No significant change was found in the numbers of cells expressing glucocorticoid receptor α and glucocorticoid receptor β in the patients who were glucocorticoid resistant. Prednisolone therapy reduced the ratio of glucocorticoid receptor α/glucocorticoid receptor β expression for the patients who were glucocorticoid sensitive to a level seen in the patients who were glucocorticoid resistant before therapy. Conclusion: Because glucocorticoid receptor β inhibits α-glucocorticoid receptor–mediated transactivation of target genes, the increased expression of glucocorticoid receptor β in inflammatory cells might be a critical mechanism for conferring glucocorticoid resistance. (J Allergy Clin Immunol 2000;105:943-50.)

Section snippets

Subjects

The study was approved by the Guy’s Hospital Ethical Committee. Nine subjects with asthma who were glucocorticoid sensitive and 6 who were glucocorticoid resistant, age and sex matched, entered into this study (Table I).

. Clinical characteristics of subjects with asthma who are glucocorticoid sensitive or glucocorticoid resistant

Empty CellGlucocorticoid sensitiveGlucocorticoid resistant
Number96
Age (y)43 ± 445 ± 8
Sex5M3M
Percent predicted FEV176 ± 471 ± 3
Percent salbutamol response*37 ± 233 ± 3
Percent

Clinical findings and total numbers of inflammatory cells

The sizes of the cell-mediated reaction in glucocorticoid-sensitive and -resistant groups have previously been reported.13 In subjects with glucocorticoid-sensitive asthma, prednisolone suppressed the cutaneous induration from 25 ± 2 mm to 10 ± 1 mm (mean ± SEM) (n = 9; P < .003). In the subjects with glucocorticoid-resistant asthma the size of the cutaneous reaction did not change significantly: 13.5 ± 2 mm during placebo administration and 12 ± 1 mm (mean ± SEM) (n = 6; P = .23) after

Discussion

We demonstrate that significantly higher numbers of inflammatory cells expressing GRβ immunoreactivity were observed in the glucocorticoid–resistant tuberculin responses as compared with those in the glucocorticoid-sensitive group after placebo therapy. In contrast, no significant difference was observed in the number of cells expressing GRα immunoreactivity between the 2 groups of patients. An 8-fold higher GRα/GRβ ratio was observed in the glucocorticoid-sensitive group when compared with the

Acknowledgements

We thank Dr Christopher Corrigan for his comments.

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Supported by the Medical Research Council and the National Asthma Campaign.

☆☆

Reprint requests: Tak Lee, ScD, FRCP, Department of Respiratory Medicine and Allergy, 5th Floor Thomas Guy House, Guy’s Hospital, London SE1 9RT, United Kingdom.

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