SEGRAs a new therapeutic option on the horizon?

Fifty years after their initial clinical use glucocorticoids (GC) are still the most important and most frequent used anti‐inflammatory agents in the treatment of acute and chronic inflammatory diseases. Unfortunately the anti‐inflammatory and immunosuppressive effects of GC are frequently accompanied by undesired side effects. Beside unknown individual factors, recent investigations have idientified molecular mechanisms of GC action that may reveal new antiinflammatory agents with a better effect/side effect profile. The effect of GC on target cells is mediated by the regulation of transcription of steroid‐responsive genes. After binding to cytosolic glucocorticoid receptors (GR) the complex translocates into the nucleus and modulates gene transcription either by a positive (transactivation) or negative (transrepression) mode of regulation. There is growing evidence that beneficial effects as well as undesired effects are related to the dissociation of these two major mechanisms, e.g. steroid diabetes and steroid induced glaucoma seems to be mainly related to transactivation mechanisms. The dissociation of these mechanisms has recently led to the development of new agents that may predominantly induce transrepression over transactivation and subsequently lead to potent anti‐inflammatory effects while displaying less dominant side effects. Indeed, transgenic mice carrying a defective GR could demonstrate the anti‐inflammatory potential of transrepression. The purpose of this presentation is to provide an up‐date on recent developments in this field.