Maps and legends: The quest for dissociated ligands of the glucocorticoid receptor

Glucocorticoids are steroid hormones that have pleiotropic effects on development, metabolism, cognitive function and other aspects of physiology. Since the demonstration more than sixty years ago of their capacity to suppress inflammation, synthetic glucocorticoids have been extremely widely used in the treatment of inflammatory diseases. However, their clinical use is limited by numerous, unpredictable and potentially serious side effects. Glucocorticoids regulate gene expression both positively and negatively. Both of these effects are mediated by the glucocorticoid receptor, a ligand-dependent transcription factor. It has become widely accepted that anti-inflammatory effects of glucocorticoids are mostly due to inhibition of transcription, whereas the activation of transcription by the glucocorticoid receptor accounts for the majority of side effects. This dogma (which we refer to as the "transrepression hypothesis") predicts the possibility of uncoupling therapeutic, anti-inflammatory effects from side effects by identifying novel, selective ligands of the glucocorticoid receptor, which preferentially mediate inhibition rather than activation of transcription. It is argued that such "dissociated" glucocorticoid receptor ligands should retain anti-inflammatory potency but cause fewer side effects. Here we critically re-examine the history and foundations of the transrepression hypothesis. We argue that it is incompatible with the complexity of gene regulation by glucocorticoids and poorly supported by experimental evidence; that it no longer aids clear thinking about the actions of the glucocorticoid receptor; and that it will not prove a fruitful basis for continued refinement and improvement of anti-inflammatory drugs that target the glucocorticoid receptor.