Importance of glucocorticoid receptors in upper and lower airways

Glucocorticoids (GCs) are the most common and effective drugs for treating inflammatory airway diseases, but some patients respond poorly to them. GC effects are mediated through the glucocorticoid receptor (GR). We present an update on the GR gene, the GR alpha and GR beta splicing variants, their translational and post-translational modifications, as well as their alterations in disease. GR alpha is ubiquitously expressed and is responsible for the induction and repression of target genes. GR beta acts as a dominant negative inhibitor of GR alpha-mediated transactivation and transrepression in certain cell types. The GR beta message is expressed at low levels in numerous tissues and its protein is only expressed in specific cell types. Increased GR beta expression has been reported in bronchial asthma, nasal polyposis and inflammatory bowel diseases (IBD), and after incubation of cells with certain proinflammatory stimuli. In addition to GR beta, other mechanisms explaining GC resistance include alterations in GR binding to ligand, nuclear translocation, and binding to GRE, and/or a defective crosstalk with transcription factors and cofactors.