Ligand-induced differentiation of glucocorticoid receptor (GR) trans-repression and transactivation: preferential targetting of NF-kappa B and lack of I-kappa B involvement

1 Glucocorticoids are highly effective in controlling chronic inflammatory diseases, such as asthma and rheumatoid arthritis, but the exact molecular mechanism of their anti-inflammatory action remains uncertain. They act by binding to a cytosolic receptor (GR) resulting in activation or repression of gene expression. This may occur via direct binding of the GR to DNA (tra nsactivation) or by inhibition of the activity of transcription factors suc h as AP-1 and NF-kappa B (transrepression). 2 The topically active steroids fluticasone propionate (EC50 = 1.8 x 10(-11 ) M) and budesonide (EC50 = 5.0 x 10(-11) M) were more potent in inhibiting GM-CSF release from A549 cells than tipredane (EC50 = 8.3 x 10(-10) M), bu tixicort (EC50 = 3.7 x 10(-8) M) and dexamethasone (EC50 = 2.2 x 10(-9) M). The anti-glucocorticoid RU486 also inhibited GM-CSF release in these cells (IC50 = 1.8 x 10(-10) M). 3 The concentration-dependent ability of fluticasone propionate (EC50 = 9.8 x 10(-10) M), budesonide ;(EC50 = 1.1 x 10(-9) M) and dexamethasone (EC50 = 3.6 x 10(-8) M) to induce transcription of the beta(2)-receptor was found to correlate with GR DNA binding and occurred at 10-100 fold higher concen trations than the inhibition of GM-CSF release. No induction of the endogen ous inhibitors of NF-kappa B, I kappa B alpha or I-kappa B beta, was seen a t 24 h and the ability of IL-1 beta to degrade and subsequently induce I ka ppa B alpha was not altered by glucocorticoids. 4 The ability of fluticasone propionate (IC50 = 0.5 x 10(-11) M), budesonid e (IC50 = 2.7 x 10(-11) M), dexamethasone (IC50 = 0.5 x 10(-9) M) and RU486 (IC50 = 2.7 x 10(-11) M) to inhibit a 3 x kappa B was associated with inhi bition of GM-CSF release. 5 These data suggest that the anti-inflammatory properties of a range of gl ucocorticoids relate to their ability to transrepress rather than transacti vate genes.