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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
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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.
Keywords
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

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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.
@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},
  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},
}

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