The effects of glucocorticoids on phorbol ester and cytokine stimulated transcription factor activation in human lung

I. M. Adcock, H. Shirasaki, C. M. Gelder, M. J. Peters, C. R. Brown, P. J. Barnes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

Glucocorticoids have a wide variety of effects which result in the dampening of inflammatory and immune responses and other challenges to homeostasis. An important site of steroid action may be on the control of transcription factor binding to DNA. The interaction of the transcription factors, activator protein 1 (AP-1) and nuclear factor kappa from B cells (NFκB) with DNA and glucocorticoid receptors was analysed by gel mobility shift assays following stimulation by tumour necrosis factor alpha (TNFα) and a phorbol ester (PMA) that activates protein kinase C. PMA and TNFα both caused significant (180-340%) increases in AP-1 and NFκB DNA binding which peaked at 15 minutes and decreased to a constant elevated level at between 1-3 hrs and was sustained for 24hrs. Dexamethasone (1μM) caused a rapid and long lasting 40-50% decrease in both AP-1 and NFκB DNA binding lasting over 24 hrs. Combined treatment with dexamethasone and PMA or TNFα prevented the increase in both AP-1 and NFκB binding due to PMA and TNFα returning levels to those seen in control untreated samples. This suggests that in human lung, the glucocorticoid receptor functionally interacts within the nucleus with other transcription factors that are induced by inflammatory mediators such as cytokines. This may be an important molecular site of steroid action in chronic inflammatory lung diseases such as asthma.

Original languageEnglish
Pages (from-to)1147-1153
Number of pages7
JournalLife Sciences
Volume55
Issue number14
DOIs
Publication statusPublished - 1994
Externally publishedYes

Keywords

  • activation protein-1
  • cross coupling
  • glucocorticoid receptors
  • lung
  • NFκB

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