NFκB and glucocorticoid receptor activity in steroid resistance

Charlotte Dawson, Ashwin Dhanda, Becky Conway-Campbell, Alexandra Dimambro, Stafford Lightman, Colin Dayan

Research output: Contribution to journalArticle (Academic Journal)

8 Citations (Scopus)

Abstract

Resistance to the anti-inflammatory and immunosuppressive effects of steroids is an important clinical problem that complicates the treatment of approximately 30% of patients with conditions for which steroids are normally first-line therapy. Previous studies have shown that steroid-resistant (SR) patients have more severe disease and higher levels of inflammatory cytokine production than steroid-sensitive (SS) patients, but the molecular mechanisms for this remain poorly understood. Peripheral blood mononuclear cells from healthy volunteers were tested for steroid resistance by their in vitro response to the anti-proliferative effects of dexamethasone. The SR cohort had high baseline levels of NFκB DNA binding activity, equivalent to that in phytohemagglutinin (PHA)-stimulated SS cells. In SR cells, dexamethasone exposure, but not PHA, increased binding of the p65 NFκB subunit to the κB promoter element. Glucocorticoid receptor (GR) was not detected at either the κB promoter element or the glucocorticoid response element (GRE), suggesting that it does not translocate to the nucleus in these cells. Conversely, in SS cells, baseline p65 DNA binding activity was low and significantly increased by PHA, but not by dexamethasone. Unlike in SR cells, GR was detected at the κB element and at the GRE. These findings suggest that in SR patients, steroids may be harmful by increasing NFκB activity which would exacerbate disease by increasing transcription of inflammatory cytokines.

Original languageEnglish
Pages (from-to)29-35
Number of pages7
JournalJournal of Receptor and Signal Transduction Research
Volume32
Issue number1
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Adult
  • Cells, Cultured
  • Cytokines
  • Dexamethasone
  • Drug Resistance
  • Female
  • Glucocorticoids
  • Humans
  • Inflammation
  • Leukocytes, Mononuclear
  • Male
  • Middle Aged
  • NF-kappa B
  • Protein Binding
  • Receptors, Glucocorticoid
  • Response Elements
  • Steroids
  • Transcription Factor RelA

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