Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-kappaB-dependent transcription.
Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-kappaB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-kappaB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IkappaB-alpha expression, but impaired the tumor necrosis factor (TNF)-alpha-induced degradation of IkappaB-alpha without affecting DNA binding of NF-kappaB. The structural requirements for the various functions of glucocorticoids are discussed.
T10 T11 T12 T13 T14 T15 T16 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-Y
GR NF-kappaB NF-kappaB GR IkappaB-alpha tumor necrosis factor (TNF)-alpha NF-kappaB steroid Betamethasone triamcinolone dexamethasone clobetasol RU486 IkappaB-alpha NF-kappaB glucocorticoid receptor