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Glucocorticoid receptor-based transrepressive mechanisms at promoters of inflammatory genes

Ilse Beck (2009)
abstract
Inflammation is designed to remove the damaging agent and to restore tissue. Mechanistically, inflammatory disease-prompted TNF production can activate the transcription factor NF-κB and NF-κB then stimulates the expression of pro-inflammatory cytokines, chemokines and adhesion molecules. Glucocorticoids, steroidal ligands of the glucocorticoid receptor (GR), can repress pro-inflammatory gene expression via interference with the composition and activity of the enhanceosome, the activity of NF-κB and/or the signalling pathway towards NF-κB activation. We explored possible crosstalk of activated GR with MSK1, an ERK- and p38 MAPK-activated kinase that can contribute to NF-κB activation via S276 phosphorylation. In TNF-stimulated cells, GCs don’t affect the MSK1 kinase activity, but abrogated H3S10 phosphorylation at pro-inflammatory gene promoters and concomitantly diminished NF-κB S276 phosphorylation. We found that GCs abolish the recruitment of activated MSK1 at inflammatory gene promoters, thus resulting in the inhibition of NF-κB p65 transactivation and of concurrent histone H3 S10 phosphorylation. However, GCs can also drive nuclear MSK1 into the cytoplasm via a GR- and CRM1-dependent anti-inflammatory mechanism concomitants with an interaction between GC-activated GR and activated MSK1. Furthermore, to counteract the detrimental side-effect profile of GCs, a combination of two anti-inflammatory compounds could be more beneficial than treatments with the sole compounds. In this respect, upon combining GCs and H89, an MSK1 inhibitor, we discovered a dose-dependent additive repression of NF-κB-driven, pro-inflammatory gene expression. Similar results were obtained by combining GCs with inhibitors ERK and p38 MAPKs. Mechanistically, the additive repression can be most likely attributed to diverse and multilayered repression mechanisms employed by GCs and MSK1 inhibitors. Finally, we identified the non-steroidal CpdA, a plant-derived phenyl aziridine precursor, as a selective GR modulator, with a more beneficial side effect-profile than classic GCs. CpdA cannot mediate GRE-regulated gene transcription; but can act as an anti-inflammatory in an acute inflammation in vivo model. Mechanistically, the inhibition of NF-κB-driven gene expression by CpdA occurs in a GR- and Hsp70-dependent manner in which CpdA hampers TNF-induced IκBα degradation, NF-κB p65 nuclear translocation and ultimately NF-κB p65-DNA binding. Moreover, CpdA can also negatively interfere with the transactivation capacity of NF-κB in the nucleus.
Please use this url to cite or link to this publication:
author
promoter
Guy Haegeman
organization
year
type
dissertation (monograph)
subject
keyword
Inflammation, NF-kB, Glucocorticoids, GR, MSK1
pages
245 pages
place of publication
Gent
defense location
Gent, Het Pand
defense date
2009-01-28 15:00
language
English
UGent publication?
yes
classification
D1
id
481375
handle
http://hdl.handle.net/1854/LU-481375
alternative location
http://lib.ugent.be/fulltxt/RUG01/001/324/722/RUG01-001324722_2010_0001_AC.pdf
date created
2009-02-05 11:59:59
date last changed
2009-02-06 11:38:42
@phdthesis{481375,
  abstract     = {Inflammation is designed to remove the damaging agent and to restore tissue. Mechanistically, inflammatory disease-prompted TNF production can activate the transcription factor NF-\ensuremath{\kappa}B and NF-\ensuremath{\kappa}B then stimulates the expression of pro-inflammatory cytokines, chemokines and adhesion molecules. Glucocorticoids, steroidal ligands of the glucocorticoid receptor (GR), can repress pro-inflammatory gene expression via interference with the composition and activity of the enhanceosome, the activity of NF-\ensuremath{\kappa}B and/or the signalling pathway towards NF-\ensuremath{\kappa}B activation.
We explored possible crosstalk of activated GR with MSK1, an ERK- and p38 MAPK-activated kinase that can contribute to NF-\ensuremath{\kappa}B activation via S276 phosphorylation. In TNF-stimulated cells, GCs don{\textquoteright}t affect the MSK1 kinase activity, but abrogated H3S10 phosphorylation at pro-inflammatory gene promoters and concomitantly diminished NF-\ensuremath{\kappa}B S276 phosphorylation. We found that GCs abolish the recruitment of activated MSK1 at inflammatory gene promoters, thus resulting in the inhibition of NF-\ensuremath{\kappa}B p65 transactivation and of concurrent histone H3 S10 phosphorylation. However, GCs can also drive nuclear MSK1 into the cytoplasm via a GR- and CRM1-dependent anti-inflammatory mechanism concomitants with an interaction between GC-activated GR and activated MSK1. 
Furthermore, to counteract the detrimental side-effect profile of GCs, a combination of two anti-inflammatory compounds could be more beneficial than treatments with the sole compounds. In this respect, upon combining GCs and H89, an MSK1 inhibitor, we discovered a dose-dependent additive repression of NF-\ensuremath{\kappa}B-driven, pro-inflammatory gene expression. Similar results were obtained by combining GCs with inhibitors ERK and p38 MAPKs. Mechanistically, the additive repression can be most likely attributed to diverse and multilayered repression mechanisms employed by GCs and MSK1 inhibitors. 
Finally, we identified the non-steroidal CpdA, a plant-derived phenyl aziridine precursor, as a selective GR modulator, with a more beneficial side effect-profile than classic GCs. CpdA cannot mediate GRE-regulated gene transcription; but can act as an anti-inflammatory in an acute inflammation in vivo model. Mechanistically, the inhibition of NF-\ensuremath{\kappa}B-driven gene expression by CpdA occurs in a GR- and Hsp70-dependent manner in which CpdA hampers TNF-induced I\ensuremath{\kappa}B\ensuremath{\alpha} degradation, NF-\ensuremath{\kappa}B p65 nuclear translocation and ultimately NF-\ensuremath{\kappa}B p65-DNA binding. Moreover, CpdA can also negatively interfere with the transactivation capacity of NF-\ensuremath{\kappa}B in the nucleus.},
  author       = {Beck, Ilse},
  keyword      = {Inflammation,NF-kB,Glucocorticoids,GR,MSK1},
  language     = {eng},
  pages        = {245},
  school       = {Ghent University},
  title        = {Glucocorticoid receptor-based transrepressive mechanisms at promoters of inflammatory genes},
  url          = {http://lib.ugent.be/fulltxt/RUG01/001/324/722/RUG01-001324722\_2010\_0001\_AC.pdf},
  year         = {2009},
}

Chicago
Beck, Ilse. 2009. “Glucocorticoid Receptor-based Transrepressive Mechanisms at Promoters of Inflammatory Genes”. Gent.
APA
Beck, I. (2009). Glucocorticoid receptor-based transrepressive mechanisms at promoters of inflammatory genes. Gent.
Vancouver
1.
Beck I. Glucocorticoid receptor-based transrepressive mechanisms at promoters of inflammatory genes. [Gent]; 2009.
MLA
Beck, Ilse. “Glucocorticoid Receptor-based Transrepressive Mechanisms at Promoters of Inflammatory Genes.” 2009 : n. pag. Print.