Alpha and beta glucocorticoid receptors: relevance in airway diseases

Glucocorticoids (GCs) are the most common and effective drugs for treating inflammatory airway respiratory diseases. Despite their efficacy, some patients respond poorly to GC treatment. Alterations in the expression of the receptor that mediates GC actions, the glucocorticoid receptor (GR), are one of the potential mechanisms that would explain GC insensitivity. In this review, we present an update on the GR gene and its products, namely GRalphaand GRbeta, as well as their alterations in disease. GRalpha has a widespread distribution and is responsible for the induction and repression of target genes, whereas GRbeta can act as a dominant negative inhibitor of GRalpha-mediated transactivation and transrepression. Very low GRbeta mRNA levels have been detected in a number of cells and tissues, which often contradict GRbeta protein data. Nevertheless, an association between GC insensitivity and increased GRbeta expression has been reported in asthma, nasal polyposis, and ulcerative colitis, and in vitro, certain pro-inflammatory cytokines upregulate GRbeta expression. However, the role of GRbeta in modulating GC sensitivity in vivo has been highly debated and is as yet unclear.