Transcriptional Potencies of Inhaled Glucocorticoids

Abstract

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.

Glucocorticoids suppress transcriptional up‐regulation of bradykinin receptors in a murine in vitro model of chronic airway inflammation

“…Actinomycin D is a transcriptional inhibitor which binds to double-helical DNA and inhibits DNA-directed RNA synthesis [25]. Dexamethasone is an inhibitor for NF-kB and AP-1 activity [26][27][28][29][30].…”

“…Glucocorticoids reduce airway hyperreactivity in the asthmatic airways [36][37][38][39] and diminish airway inflammation via inhibition of the transcription factors AP-1 and NF-kB activities [28,29,[33][34][35]. Dexamethasone inhibits the inducible bradykinin receptor expression in cultured human airway fibroblasts and smooth muscle cells [15,16].…”

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

“…18 Our findings that FP is able to increase the anti-CD3-stimulated T-cell apoptosis differently than the effects exerted by dexamethasone on T-cell hybridomas confirms that FP is a more effective steroid in exerting a proapoptotic activity on CD3-stimulated T cells. 22 Another possible explanation of this different response might also be related to the use of a different T-cell target. Similar to the effects exerted on resting T cells, the addition of salmeterol to FP was able to significantly increase the anti-CD3-stimulated PBT apoptosis in comparison with both FP and salmeterol alone, suggesting that the proapoptotic effects of combined treatment also occur on activated PBTs.…”

Corticosteroid effects on cell signalling

“…Furthermore, some steroids, such as the antagonist RU486, exhibit greater trans-repression than trans-activation effects. Indeed, the topical steroids used in asthma therapy today, such as fluticasone propionate and budesonide, appear to show more potent trans-repression than trans-activation effects, which may account for their selection as potent antiinflammatory agents [104,105]. Recently, a novel class of steroids has been described, in which there is potent transrepression with relatively little trans-activation.…”