Nuclear bioavailability of the glucocorticoid receptor in a pediatric asthma cohort with variable corticosteroid...

Despite the overall effectiveness of glucocorticoids (GCs) in the treatment of asthma, a large proportion of patients do not fully respond to this medication. The objective of the present study was to investigate the potential molecular mechanisms responsible for corticosteroid insensitivity in pediatric asthma.

Asthmatic children were classified as good (GSR) or poor corticosteroid responders (PSR) based on the changes in pulmonary function following GC treatment. Immortalized B-cells derived from patients at two ends of the spectrum of GC responsiveness (five each) were grown in culture and treated with hydrocortisone (10(-6)M). Baseline and temporal changes in GC receptor (GR) protein and mRNA were evaluated by western blot and quantitative reverse transcription PCR respectively. The effect of GC treatment on GR nuclear levels was assessed by western blots.

Cells derived from PSR asthmatics displayed lower GR protein levels when compared to GSR. Moreover, in PSR cells GC-induced nuclear translocation of GR was short-lived and homologous downregulation of GR mRNA and protein was faster than in GSR.

Our data demonstrate the existence of a novel mechanism of GC insensitivity resulting from limited GR nuclear bioavailability as a consequence of decreased baseline GR protein expression and more rapid hormone-induced downregulation.