Increased Glucocorticoid Receptor β in Airway Cells of Glucocorticoid-insensitive Asthma

Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem that can be associated with life-threatening disease progression. The molecular basis of GC insensitivity is unknown. Alternative splicing of the GC receptor (GCR) pre-mRNA generates a second GCR, termed GCR β , which does not bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCR β could account for glucocorticoid insensitivity. Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCR β immunoreactivity using a GCR β -specific antibody by immunohistochemical staining. Cell localization of GCR β expression was performed using a double immunostaining technique. Patients with GC-insensitive asthma expressed a significantly higher number of GCR β -immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects. Furthermore, GCR β expression in GC-insensitive asthma was particularly high in airway T cells, which are thought to play a major role in the pathogenesis of asthma. We also examined the expression of GCR β in specimens from the airways of patients with chronic bronchitis. In chronic bronchitis, few cells were GCR β -positive and their numbers did not differ significantly from normal control subjects. We conclude that GC-insensitive asthma is associated with increased expression of GCR β in airway T cells.