TY - JOUR
T1 - Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands
AU - Löwenberg, Mark
AU - Stahn, Cindy
AU - Hommes, Daniel W.
AU - Buttgereit, Frank
PY - 2008
Y1 - 2008
N2 - Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant agents. Unfortunately, they also produce serious side effects that limit their usage. This discrepancy is the driving force for the intensive search for novel GC receptor ligands with a better benefit-risk ratio as compared to conventional GCs. A better understanding of the molecular mode of GC action might result in the identification of novel drug targets. Genomic GC effects are mediated by transrepression or transactivation, the latter being largely responsible for GC side effects. We here discuss novel GC receptor ligands, such as selective glucocorticoid receptor agonists (SEGRAs), which might optimize genomic GC effects as they preferentially induce transrepression with little or no transactivating activity. In addition to genomic GC effects, GCs also produce rapid genomic-independent activities, termed nongenomic, and we here review the possible implications of a recently reported mechanism underlying nongenomic GC-induced immunosuppression in T cells. It was shown that the synthetic GC dexamethasone targets membrane-bound GC receptors leading to impaired T cell receptor signaling. As a consequence, membrane-linked GC receptors might be a potential candidate target for GC therapy. The ultimate goal is to convert these molecular insights into new GC receptor modulators with an improved therapeutic index
AB - Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant agents. Unfortunately, they also produce serious side effects that limit their usage. This discrepancy is the driving force for the intensive search for novel GC receptor ligands with a better benefit-risk ratio as compared to conventional GCs. A better understanding of the molecular mode of GC action might result in the identification of novel drug targets. Genomic GC effects are mediated by transrepression or transactivation, the latter being largely responsible for GC side effects. We here discuss novel GC receptor ligands, such as selective glucocorticoid receptor agonists (SEGRAs), which might optimize genomic GC effects as they preferentially induce transrepression with little or no transactivating activity. In addition to genomic GC effects, GCs also produce rapid genomic-independent activities, termed nongenomic, and we here review the possible implications of a recently reported mechanism underlying nongenomic GC-induced immunosuppression in T cells. It was shown that the synthetic GC dexamethasone targets membrane-bound GC receptors leading to impaired T cell receptor signaling. As a consequence, membrane-linked GC receptors might be a potential candidate target for GC therapy. The ultimate goal is to convert these molecular insights into new GC receptor modulators with an improved therapeutic index
U2 - https://doi.org/10.1016/j.steroids.2007.12.002
DO - https://doi.org/10.1016/j.steroids.2007.12.002
M3 - Article
C2 - 18221974
SN - 0039-128X
VL - 73
SP - 1025
EP - 1029
JO - Steroids
JF - Steroids
IS - 9-10
ER -