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

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Abstract
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 (transactivation) or by inhibition of the activity of transcription factors such as AP‐1 and NF‐κB (transrepression). The topically active steroids fluticasone propionate (EC50=1.8×10−11 M) and budesonide (EC50=5.0×10−11 M) were more potent in inhibiting GM‐CSF release from A549 cells than tipredane (EC50=8.3×10−10 M), butixicort (EC50=3.7×10−8 M) and dexamethasone (EC50=2.2×10−9 M). The anti‐glucocorticoid RU486 also inhibited GM‐CSF release in these cells (IC50=1.8×10−10 M). The concentration‐dependent ability of fluticasone propionate (EC50=9.8×10−10 M), budesonide (EC50=1.1×10−9 M) and dexamethasone (EC50=3.6×10−8 M) to induce transcription of the β2‐receptor was found to correlate with GR DNA binding and occurred at 10–100 fold higher concentrations than the inhibition of GM‐CSF release. No induction of the endogenous inhibitors of NF‐κB, IκBα or I‐κBβ, was seen at 24 h and the ability of IL‐1β to degrade and subsequently induce IκBα was not altered by glucocorticoids. The ability of fluticasone propionate (IC50=0.5×10−11 M), budesonide (IC50=2.7×10−11 M), dexamethasone (IC50=0.5×10−9 M) and RU486 (IC50=2.7×10−11 M) to inhibit a 3×κB was associated with inhibition of GM‐CSF release. These data suggest that the anti‐inflammatory properties of a range of glucocorticoids relate to their ability to transrepress rather than transactivate genes. British Journal of Pharmacology (1999) 127, 1003–1011; doi:10.1038/sj.bjp.0702613