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 beta, which does not bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCR beta could account for glucocorticoid insensitivity. Bronchoalveolar ravage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCR beta immunoreactivity using a GCR beta-specific antibody by immunohistochemical staining. Cell localization of GCR beta expression was performed using a double immunostaining technique. Patients with GC-insensitive asthma expressed a significantly higher number of GCR beta-immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects. Furthermore, GCR beta 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 beta in specimens from the airways of patients with chronic bronchitis. In chronic bronchitis, few cells were GCR beta-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 beta in airway T cells.