Minireview: latest perspectives on antiinflammatory actions of glucocorticoids

Abstract

Taking into consideration that glucocorticoid (GC) hormones have been used clinically for over half a century and that more than 20 yr have passed since the cloning of the GC receptor (GR), it is hard to imagine that novel aspects in the molecular mechanism by which GCs mediate their antiinflammatory actions are still being unveiled today. Partly, this is because almost on a daily basis, novel insights arise from parallel fields, e.g. nuclear receptor cofactor and chromatin regulation and their concomitant impact on gene transcription events, eventually leading to a revisitation or refinement of old hypotheses. On the other hand, it does remain striking and puzzling why GCs use different mechanisms in so many different cell types and on many different target genes to elicit an antiinflammatory effect. Meanwhile, the obvious question for the clinic remains: is the separation of GR functionalities through differential ligand design the strategy of choice to avoid most GC-mediated side effects? This minireview aims to highlight some of the latest findings on aspects of the antiinflammatory working mechanisms of GCs.

Fig. 1.

What steroid pharmacologists are aiming for, based on GR. Classical GCs, e.g. DEX and triamcinolone, elicit transrepression and transactivation mechanisms equally well. The latter event is deemed responsible for many unwanted effects, the so-called metabolic side effects. Dissociated steroidal ligands have been developed and are still being developed, which should mainly focus on the transrepression mechanism and stimulate the side effect pathway to a lesser extent, at least in specific tissues (smaller picture on the right), e.g. RU24858 and AL-438 (26 31 40 41 42 43 44 ). A newer generation of antiinflammatory drugs includes the nonsteroidal dissociated GR modulators. So far, they have shown promising benefit to side effect ratios, e.g. ZK216348 (27 ) and CpdA (24 29 ). The X means that in this category, some of them do not support transactivation. For example, for the plant-derived GR modulator CpdA, no GRE-dependent gene stimulation has been found so far, in vitro and in vivo (24 29 ). Note that the different ligands are able to impose different receptor conformations, partially explaining their differential effects on gene regulation.

Fig. 2.

Targets of GR for immunomodulation. Hormone-activated GR is able to negatively regulate the activity of various other DNA-bound transcription factors, including among others NF-κB, CREB, IRF3, NFAT, STAT, T-Bet, GATA-3, and AP-1, via the transrepression mechanism or so-called tethering mechanism (factors inside circle). For AP-1, it has been described that GR can either negatively or positively influence its activity, depending on the composition of this dimer (see text for details). The pleiotropic GR is further capable of exerting its immune system modulatory effects through additional mechanisms (events depicted outside the circle). pol II, RNA polymerase II; TCR, T cell receptor. Arrow, Activating signal; blocked arrow, inhibitory signal; round arrow, modulatory signal, which can be either activating or inhibitory depending on the context, e.g. the loss of a coactivator or the recruitment of a corepressor molecule.