Oxidative stress modulates theophylline effects on steroid responsiveness

John A. Marwick, Gillian Wallis, Koremu Meja, Bernhard Kuster, Tewis Bouwmeester, Probir Chakravarty, Danielle Fletcher, Paul A. Whittaker, Peter J. Barnes, Kazuhiro Ito, Ian M. Adcock, Paul A. Kirkham

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Oxidative stress is a central factor in many chronic inflammatory diseases such as severe asthma and chronic obstructive pulmonary disease (COPD). Oxidative stress reduces the anti-inflammatory corticosteroid action and may therefore contribute to the relative corticosteroid insensitivity seen in these diseases. Low concentrations of theophylline can restore the anti-inflammatory action of corticosteroids in oxidant exposed cells, however the mechanism remains unknown. Here, we demonstrate that a low concentration of theophylline restores corticosteroid repression of pro-inflammatory mediator release and histone acetylation in oxidant exposed cells. Global gene expression analysis shows that theophylline regulates distinct pathways in naïve and oxidant exposed cells and reverses oxidant mediated modulated of pathways. Furthermore, quantitative chemoproteomics revealed that theophylline has few high affinity targets in naive cells but an elevated affinity in oxidant stressed cells. In conclusion, oxidative stress alters theophylline binding profile and gene expression which may result in restoration of corticosteroid function.

Original languageEnglish
Pages (from-to)797-802
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume377
Issue number3
DOIs
StatePublished - 19 Dec 2008
Externally publishedYes

Keywords

  • Corticosteroid insensitivity
  • Histone acetylation
  • Histone deacetylase 2
  • Oxidative stress
  • Theophylline

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