MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium

被引:73
作者
Fuerst, Robert
Schroeder, Timm
Eilken, Hanna M.
Bubik, Martin F.
Kiemer, Alexandra K.
Zahler, Stefan
Vollmar, Angelika M.
机构
[1] Univ Munich, Dept Pharm, D-81377 Munich, Germany
[2] GSF, Natl Res Ctr Environm & Hlth, Inst Stem Cell Res, Neuherberg, Germany
[3] Univ Saarland, Inst Pharmaceut Biol, D-6600 Saarbrucken, Germany
关键词
inflammation;
D O I
10.1096/fj.06-6752com
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition of proinflammatory transcription factors like NF-kappa B. In recent years, however, transcription factor-independent mechanisms of glucocorticoid action have been proposed, namely the influence on MAPK pathways. Here we identify MAPK phosphatase-1 ( MKP-1) as a pivotal mediator of the anti-inflammatory action of glucocorticoids in the human endothelium. We applied dexamethasone ( Dex) to TNF-alpha-activated human endothelial cells and used the adhesion molecule E-selectin as inflammatory read-out parameter. Dex is known to reduce the expression of E-selectin, which is largely regulated by NF-kappa B. Here, we communicate that Dex at low concentrations ( 1 - 100 nM) markedly attenuates E-selectin expression without affecting NF-kappa B. Importantly, Dex is able to increase the expression of MKP-1, which causes an inactivation of TNF-alpha-induced p38 MAPK and mediates inhibition of E-selectin expression. In endothelial MKP-1(-/-) cells differentiated from MKP-1(-/-) embryonic stem cells and in MKP-1-silenced human endothelial cells, Dex did not inhibit TNF-alpha-evoked E-selectin expression. Thus, our findings introduce MKP-1 as a novel and crucial mediator of the anti-inflammatory action of glucocorticoids at low concentrations in the human endothelium and highlight MKP-1 as an important and promising anti-inflammatory drug target.
引用
收藏
页码:74 / 80
页数:7
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