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Glucocorticoids and mitogen- and stress-activated protein kinase 1 inhibitors: Possible partners in the combat against inflammation

Ilse Beck UGent, Wim Vanden Berghe UGent, Sarah Gerlo UGent, Nadia Bougarne UGent, Linda Vermeulen UGent, Karolien De Bosscher UGent and Guy Haegeman UGent (2009) BIOCHEMICAL PHARMACOLOGY. 77(7). p.1194-1205
abstract
In the combat against inflammation, glucocorticoids (GCs) are a widespread therapeutic. These ligands of the glucocorticoid receptor (GR) inhibit the transactivation of various transcription factors, including nuclear factor-kappa B (NF-kappa B), and alter the composition of the pro-inflammatory enhanceosome, culminating in the repression of pro-inflammatory gene expression. However, pharmacological usage of GCs in long-term treatment is burdened with a detrimental side-effect profile. Recently, we discovered that GCs can lower NF-kappa B transactivation. and pro-inflammatory gene expression by abolishing the recruitment of mitogen- and stress-activated protein kinase 1 (MSK1) (EC 2.7.11.1) to pro-inflammatory gene promoters and displacing a significant fraction of MSK1 to the cytoplasm. In our current investigation in L929sA fibroblasts, upon combining GCs and MSK1 inhibitors, we discovered a dose-dependent additive repression of pro-inflammatory gene expression, most likely due to diverse and multilayered repression mechanisms employed by GCs and MSK1 inhibitors. Therefore, the combined application of GCs and MSK1 inhibitors enabled a similar level of repression of pro-inflammatory gene expression, using actually a lower concentration of GCs and MSK1 inhibitors combined than would be necessary when using these inhibitors separately. Although H89 can inhibit both MSK1 and PKA, TNF does not activate PKA (EC 2.7.11.11) and as such PKA inhibition does not mediate H89-instigated repression of TNF-stimulated gene expression. Furthermore, the additional repressive effects of liganded GR and inhibition of MSK1, are not mediated via GR transactivation mechanisms. In conclusion, these results could entail a new therapeutic strategy using lower drug concentrations, potentially leading to a more beneficial side-effect profile.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
SER(276) PHOSPHORYLATION, NUCLEAR RECEPTORS, TRANSCRIPTIONAL ACTIVATION, GENE-EXPRESSION, NF-KAPPA-B, Inflammation, NF-kappa B, PKA, MSK1, Glucocorticoids, GR, MAP KINASE, CROSS-TALK, REPRESSION, P38
journal title
BIOCHEMICAL PHARMACOLOGY
Biochem. Pharmacol.
volume
77
issue
7
pages
1194 - 1205
publisher
PERGAMON-ELSEVIER SCIENCE LTD
place of publication
OXFORD , ENGLAND
Web of Science type
Article
Web of Science id
000264457500008
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
4.254 (2009)
JCR rank
34/236 (2009)
JCR quartile
1 (2009)
ISSN
0006-2952
DOI
10.1016/j.bcp.2008.12.008
language
English
UGent publication?
yes
classification
A1
id
671766
handle
http://hdl.handle.net/1854/LU-671766
date created
2009-05-29 11:52:51
date last changed
2009-06-04 09:53:36
@article{671766,
  abstract     = {In the combat against inflammation, glucocorticoids (GCs) are a widespread therapeutic. These ligands of the glucocorticoid receptor (GR) inhibit the transactivation of various transcription factors, including nuclear factor-kappa B (NF-kappa B), and alter the composition of the pro-inflammatory enhanceosome, culminating in the repression of pro-inflammatory gene expression. However, pharmacological usage of GCs in long-term treatment is burdened with a detrimental side-effect profile. Recently, we discovered that GCs can lower NF-kappa B transactivation. and pro-inflammatory gene expression by abolishing the recruitment of mitogen- and stress-activated protein kinase 1 (MSK1) (EC 2.7.11.1) to pro-inflammatory gene promoters and displacing a significant fraction of MSK1 to the cytoplasm. In our current investigation in L929sA fibroblasts, upon combining GCs and MSK1 inhibitors, we discovered a dose-dependent additive repression of pro-inflammatory gene expression, most likely due to diverse and multilayered repression mechanisms employed by GCs and MSK1 inhibitors. Therefore, the combined application of GCs and MSK1 inhibitors enabled a similar level of repression of pro-inflammatory gene expression, using actually a lower concentration of GCs and MSK1 inhibitors combined than would be necessary when using these inhibitors separately. Although H89 can inhibit both MSK1 and PKA, TNF does not activate PKA (EC 2.7.11.11) and as such PKA inhibition does not mediate H89-instigated repression of TNF-stimulated gene expression. Furthermore, the additional repressive effects of liganded GR and inhibition of MSK1, are not mediated via GR transactivation mechanisms. In conclusion, these results could entail a new therapeutic strategy using lower drug concentrations, potentially leading to a more beneficial side-effect profile.},
  author       = {Beck, Ilse and Vanden Berghe, Wim and Gerlo, Sarah and Bougarne, Nadia and Vermeulen, Linda and De Bosscher, Karolien and Haegeman, Guy},
  issn         = {0006-2952},
  journal      = {BIOCHEMICAL PHARMACOLOGY},
  keyword      = {SER(276) PHOSPHORYLATION,NUCLEAR RECEPTORS,TRANSCRIPTIONAL ACTIVATION,GENE-EXPRESSION,NF-KAPPA-B,Inflammation,NF-kappa B,PKA,MSK1,Glucocorticoids,GR,MAP KINASE,CROSS-TALK,REPRESSION,P38},
  language     = {eng},
  number       = {7},
  pages        = {1194--1205},
  publisher    = {PERGAMON-ELSEVIER SCIENCE LTD},
  title        = {Glucocorticoids and mitogen- and stress-activated protein kinase 1 inhibitors: Possible partners in the combat against inflammation},
  url          = {http://dx.doi.org/10.1016/j.bcp.2008.12.008},
  volume       = {77},
  year         = {2009},
}

Chicago
Beck, Ilse, Wim Vanden Berghe, Sarah Gerlo, Nadia Bougarne, Linda Vermeulen, Karolien De Bosscher, and Guy Haegeman. 2009. “Glucocorticoids and Mitogen- and Stress-activated Protein Kinase 1 Inhibitors: Possible Partners in the Combat Against Inflammation.” Biochemical Pharmacology 77 (7): 1194–1205.
APA
Beck, I., Vanden Berghe, W., Gerlo, S., Bougarne, N., Vermeulen, L., De Bosscher, K., & Haegeman, G. (2009). Glucocorticoids and mitogen- and stress-activated protein kinase 1 inhibitors: Possible partners in the combat against inflammation. BIOCHEMICAL PHARMACOLOGY, 77(7), 1194–1205.
Vancouver
1.
Beck I, Vanden Berghe W, Gerlo S, Bougarne N, Vermeulen L, De Bosscher K, et al. Glucocorticoids and mitogen- and stress-activated protein kinase 1 inhibitors: Possible partners in the combat against inflammation. BIOCHEMICAL PHARMACOLOGY. OXFORD , ENGLAND: PERGAMON-ELSEVIER SCIENCE LTD; 2009;77(7):1194–205.
MLA
Beck, Ilse, Wim Vanden Berghe, Sarah Gerlo, et al. “Glucocorticoids and Mitogen- and Stress-activated Protein Kinase 1 Inhibitors: Possible Partners in the Combat Against Inflammation.” BIOCHEMICAL PHARMACOLOGY 77.7 (2009): 1194–1205. Print.