The physiology of human glucocorticoid receptor beta (hGRbeta) and glucocorticoid resistance.

The development of glucocorticoid (GC) resistance is a serious problem that complicates the treatment of immune-related diseases, such as asthma, ulcerative colitis, and hematologic cancers. hGRalpha and hGRbeta are two isoforms of the human glucocorticoid receptor, which differ in the structural composition of the carboxy-terminal end of the ligand-binding domain and therefore in their ability to bind glucocorticoid ligand and in their physiological function. hGRalpha is the classically functional GR, while hGRbeta seems to act mainly as a dominant negative to the function of hGRalpha. Because of the ability of hGRbeta to antagonize the action of hGRalpha, it has been hypothesized that changes in the expression of hGRbeta may underlie the development of glucocorticoid resistance. In this article we review what is known about the expression and physiological action of hGRbeta in normal cells and tissue as well as in several disease states. Taken together, the evidence suggests that the ratio of hGRalpha:hGRbeta expression is indeed critical to the glucocorticoid responsiveness of various cells. This ratio can be altered by changing the expression level of hGRalpha, hGRbeta, or both receptors simultaneously. Higher ratios correlate with glucocorticoid sensitivity, while lower ratios correlate with glucocorticoid resistance. Thus hGRbeta can be an important modulator of glucocorticoid responsiveness.