Background Glucocorticoids exert their anti-inflammatory effects mainly through transrepression of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB). Certain adverse effects of glucocorticoids are mediated through gene transactivation. Fluticasone propionate (FP) and mometasone furoate (MF) are the most recently developed topical glucocorticoids for the treatment of airway disorders. Their relative capacities to repress AP-1 and NF-κB activities are not known and comparison of their transactivation potencies has given unclear results.
Objective To determine the relative transactivation and transrepression potencies of FP and MF.
Methods Transactivation assays were performed in HeLa cells carrying a glucocorticoid-inducible luciferase gene. To measure transrepressive potencies of FP and MF, A549 lung epithelial cells were transiently transfected with an AP-1- or NF-κB-dependent luciferase gene. Using an immunoassay, we also evaluated the ability of MF and FP to inhibit the production of Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES), a pro-inflammatory cytokine, whose gene is controlled by AP-1 and NF-κB. Areas under the dose–response curve were calculated to determine relative potencies.
Results FP and MF are equipotent for transactivation. Both molecules show globally the same potency to inhibit AP-1 and NF-κB activities and RANTES production. MF and FP have very significant transcriptional effects at 2×10−10 M, which is the peak concentration reached in the plasma after inhalation of high dosages. Indeed, they produce a 17-fold induction of luciferase in the transactivation assay, and inhibit AP-1 activity, NF-κB activity and RANTES release by approximately 40%.
Conclusion FP and MF have the same ability to trigger gene activation and also the same potency to inhibit AP-1 and NF-κB activities. Their strong transcriptional effects at 2×10−10 M suggest that these compounds act not only topically but also systemically, with the risk of provoking concomitant adverse effects at high dosages.