The glucocorticoid receptor in inflammatory processes: transrepression is not enough

Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of anti-inflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile.