Transcriptional potencies of inhaled glucocorticoids.
Glucocorticoids (GC) are the most effective anti-inflammatory drugs used in asthma. By a process called trans-activation, they increase the transcription of genes involved in either beneficial processes or certain side effects. Through trans-repression, they inhibit the transcription factors nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1), thereby decreasing the expression of many genes encoding inflammatory mediators such as the cytokine RANTES. We have measured the trans-activation and trans-repression potencies of the five currently available inhaled GC using reporter gene assays. The rank order of trans-activation potencies in HeLa cells stably transfected with a GC-inducible luciferase gene was fluticasone propionate > budesonide and triamcinolone acetonide > beclomethasone dipropionate and flunisolide. For all GC except beclomethasone dipropionate, there was a highly significant correlation between their potency to trans-activate in HeLa cells and their capacity to induce the gluconeogenic enzyme tyrosine aminotransferase in hepatoma tissue culture (HTC) cells. The rank order of trans-repression potencies in A549 lung cells transiently transfected with an AP-1- or NF-kappaB-dependent luciferase gene was fluticasone propionate > budesonide > beclomethasone dipropionate, triamcinolone acetonide, and flunisolide. The same rank order was found for inhibition of RANTES release. Thus, determination of trans-repression and trans-activation potencies of GC may help to predict their capacity to produce anti-inflammatory and side effects, respectively.
Jaffuel
D
D
Institut National de la Santé et de la Recherche Médicale U454 and Service des Maladies Respiratoires, Montpellier, France.
Demoly
P
P
Gougat
C
C
Balaguer
P
P
Mautino
G
G
Godard
P
P
Bousquet
J
J
Mathieu
M
M
D000280:Administration, Inhalation; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics; D015756:Genes, tat / Q000187:drug effects / Q000235:genetics; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*
D018946:Chemokine CCL5; D005938:Glucocorticoids; D016328:NF-kappa B; D018808:Transcription Factor AP-1