Abstract
For over 70 years, the unique anti-inflammatory properties of glucocorticoids (GCs), which mediate their effects via the ligand-activated transcription factor, the glucocorticoid receptor alpha (GRα), have allowed for the use of these steroid hormones in the treatment of various autoimmune and inflammatory-linked diseases. However, aside from the onset of severe side-effects, chronic GC therapy often leads to the ligand-mediated downregulation of the GRα which, in turn, leads to a decrease in GC sensitivity, and effectively, the development of acquired GC resistance. Although the ligand-mediated downregulation of GRα is well documented, the precise factors which influence this process are not well understood and, thus, the development of an acquired GC resistance presents an ever-increasing challenge to the pharmaceutical industry. Recently, however, studies have correlated the dimerization status of the GRα with its ligand-mediated downregulation. Therefore, the current review will be discussing the major role-players in the homologous downregulation of the GRα pool, with a specific focus on previously reported GC-mediated reductions in GRα mRNA and protein levels, the molecular mechanisms through which the GRα functional pool is maintained and the possible impact of receptor conformation on GC-mediated GRα downregulation.
Highlights
The pharmacological use of glucocorticoids (GCs) can be traced back over a century to the work of the clinical physician, Solomon Solis-Cohen, who reported on the therapeutic benefits of orally administered adrenal gland extracts in the treatment of asthma [1]
While the ligand-independent regulation of GRα levels occurs [31,32,80], the current review focuses on the molecular mechanism through which GCs mediate the downregulation of the GRα
While it has long been known that GCs regulate the GRα pool at several levels and through various molecular mechanisms, recent studies have elucidated the dimerization-dependent nature of some of these regulatory processes [68,69,121,176,187]
Summary
The pharmacological use of glucocorticoids (GCs) can be traced back over a century to the work of the clinical physician, Solomon Solis-Cohen, who reported on the therapeutic benefits of orally administered adrenal gland extracts in the treatment of asthma [1]. Merck and company began the commercial production of the synthetic GC, cortisone and, in 1950, Kendall and Hench, together with Swiss biochemist, Tadeus Reichard, received the Nobel Prize in Physiology and Medicine for their work regarding adrenal hormones [2] This catapulted GCs into the limelight and these synthetic steroids quickly became the mainstay therapeutic choice in the treatment of auto-immune and inflammatory-linked conditions [8,9]. While it soon became apparent that this approach was a gross over-simplification of GRα signaling, the strategy would give rise to the development of selective glucocorticoid receptor agonists (SEGRAs) and selective glucocorticoid receptor modulators (SEGRMs) These ligands, which are collectively referred to as SEGRAMS, were essentially designed to preferentially induce monomeric signaling of the GC-GRα complex, over dimeric signaling, in an effort to retain the potent anti-inflammatory properties of GCs while limiting the many undesirable side effects [8,15,23,24]. The current review will be discussing the major role-players in the homologous downregulation of the GRα pool, with a specific focus on previously reported GC-mediated reductions in GRα mRNA and protein levels, the molecular mechanisms through which the GRα functional pool is maintained and the possible impact of receptor conformation on GC mediated GRα downregulation
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