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 f ailure of corticosteroids to suppress key asthma-relevant, cell-mediated in flammatory responses in the airways. Objective: The mechanism of this phenomenon is not clear but may involve ab errant 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 resista nt after 9 days of therapy with oral prednisolone (40 mg/day) or matching p lacebo in a random order, crossover design, Results: After placebo therapy, the mean numbers of cells expressing glucoc orticoid receptor alpha immunoreactivity in the lesions evoked in glucocort icoid-sensitive and -resistant patients with asthma were statistically equi valent. The numbers of cells expressing glucocorticoid receptor beta were s ignificantly elevated in the patients who were glucocorticoid resistant, re sulting 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 wi th a significant decrease in the numbers of cells expressing glucocorticoid receptor alpha but not glucocorticoid receptor beta in the subjects who we re glucocorticoid sensitive. No significant change was found in the numbers of cells expressing glucocorticoid receptor alpha and glucocorticoid recep tor beta in the patients who were glucocorticoid resistant. Prednisolone th erapy reduced the ratio of glucocorticoid receptor alpha/glucocorticoid rec eptor beta expression for the patients who were glucocorticoid sensitive to a level seen in the patients who were glucocorticoid resistant before ther apy. Conclusion: Because glucocorticoid receptor beta inhibits alpha-glucocortic oid receptor-mediated transactivation of target genes, the increased expres sion of glucocorticoid receptor beta in inflammatory cells might be a criti cal mechanism for conferring glucocorticoid resistance.