Fluticasone propionate and mometasone furoate have equivalent transcriptional potencies.
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-kappaB). 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-kappaB 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-kappaB-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-kappaB. 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-kappaB activities and RANTES production. MF and FP have very significant transcriptional effects at 2x10(-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-kappaB activity and RANTES release by approximately 40%.


CONCLUSIONS
FP and MF have the same ability to trigger gene activation and also the same potency to inhibit AP-1 and NF-kappaB activities. Their strong transcriptional effects at 2x10(-10) M suggest that these compounds act not only topically but also systemically, with the risk of provoking concomitant adverse effects at high dosages.
Roumestan
C
C
Institut National de la Santé et de la Recherche Médicale U454-IFR3, Hôpital Arnaud de Villeneuve, Montpellier, France.
Henriquet
C
C
Bousquet
J
J
Mathieu
M
M
D000730:Androstadienes / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000068298:Fluticasone; D006367:HeLa Cells; D006801:Humans; D000068656:Mometasone Furoate; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011244:Pregnadienediols / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D018946:Chemokine CCL5; D016328:NF-kappa B; D011244:Pregnadienediols; D018808:Transcription Factor AP-1; D000068656:Mometasone Furoate; D000068298:Fluticasone