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

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-kappaB (NF-kappaB), 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-kappaB 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.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Beck IM,Vanden Berghe W,Gerlo S,Bougarne N,Vermeulen L,De Bosscher K,Haegeman G

doi

10.1016/j.bcp.2008.12.008

subject

Has Abstract

pub_date

2009-04-01 00:00:00

pages

1194-205

issue

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(08)00898-8

journal_volume

pub_type

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