Transrepression and transactivation potencies of inhaled glucocorticoids
The anti-inflammatory activity of inhaled glucocorticoids is primarily mediated through transrepression of pro-inflammatory transcription factors such as Ap-1 and Nf-κB, while systemic side effects are largely attributed to transactivation via glucocorticoid response elements
(Gre) in the promoter region of responsive genes. The objective of this study is to investigate whether inhaled corticosteroids exhibit differences in their transactivation and transrepression potencies. A549 human alveolar epithelial type Ii like cells, stably transfected with a reporter
plasmid containing an Ap-1, Nf-κB or Gre induced secreted alkaline phosphatase reporter gene (Seap), were exposed to a panel of concentrations of the six inhaled and three systemic glucocorticoids. Glucocorticoid-induced changes in Seap expression were quantified by chemiluminescence.
For eight glucocorticoids (budesonide, desisobutyryl-ciclesonide, dexamethasone, flunisolide, fluocortolone, fluticasone propionate, mometasone furoate, prednisolone) the Ec50 for Nf-κB mediated transrepression was significantly larger than that for both transactivation and
transrepression via Ap-1. For the remaining glucocorticoid (triamcinolone acetonide), it was greater than that for transactivation. It is concluded that, within the studied cell system, inhaled corticosteroids did not exhibit preferential transrepression, but had higher potencies for transactivation
than for transrepression via Nf-κB and had differential potencies for the two transrepression pathways.
Document Type: Research Article
Affiliations: 1: Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA 2: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA 3: Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 874 Union Avenue, Suite 5p, Memphis, Tennessee, Tn 38163, USA, Email: [email protected]
Publication date: 01 December 2008
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