It takes two to tango: dimerisation of glucocorticoid receptor and its anti-inflammatory functions

For a number of years, there has been a widespread view that the adverse side-effects of prolonged glucocorticoid (GC) treatment are a result of glucocorticoid receptor (GR)-mediated gene activation, whilst the beneficial anti-inflammatory effects result from GR-mediated 'transrepression'. Since the introduction of the dimerisation-deficient GR mutant, GR(dim), was apparently unable to activate gene transcription, yet still able to repress pro-inflammatory gene transcription, the search for novel GR modulators has centred on the separation of gene activation from repression by prevention of GR dimerisation. However, recent work has questioned the conclusions drawn from these early GR(dim) studies, with evidence that GR(dim) mutants not only activate gene transcription, but that, in direct contradiction to the initial GR(dim) work, are also capable of forming dimers. This review of the current literature highlights the versatility of the GR in forming homodimer interactions, as well as the ability to bind to alternate nuclear receptors, and investigates the potential implications such varying GR dimer conformations may have for the design of GR ligands with a safer side effect profile.