Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma

Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem th at can be associated with life-threatening disease progression. The molecul ar basis of GC insensitivity is unknown. Alternative splicing of the GC rec eptor (GCR) pre-mRNA generates a second GCR, termed GCR beta, which does no t bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCR beta could account for glucocorticoid inse nsitivity. Bronchoalveolar ravage (BAL) cells and peripheral blood mononucl ear cells (PBMC) were examined for GCR beta immunoreactivity using a GCR be ta-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 exp ression in GC-insensitive asthma was particularly high in airway T cells, w hich are thought to play a major role in the pathogenesis of asthma. We als o examined the expression of GCR beta in specimens from the airways of pati ents with chronic bronchitis. In chronic bronchitis, few cells were GCR bet a-positive and their numbers did not differ significantly from normal contr ol subjects. We conclude that GC-insensitive asthma is associated with incr eased expression of GCR beta in airway T cells.