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Am. J. Respir. Crit. Care Med., Volume 162, Number 1, July 2000, 57-63

Transcriptional Potencies of Inhaled Glucocorticoids

DANY JAFFUEL, PASCAL DEMOLY, CLAIRE GOUGAT, PATRICK BALAGUER, GISÈLE MAUTINO, PHILIPPE GODARD, JEAN BOUSQUET, and MARC MATHIEU

Institut National de la Santé et de la Recherche Médicale U454 and Service des Maladies Respiratoires, Montpellier, France; and Institut National de la Santé et de la Recherche Médicale U439, Montpellier, France

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-kappa B) 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-kappa B-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.




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