Journal
FASEB JOURNAL
Volume 21, Issue 1, Pages 74-80Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.06-6752com
Keywords
inflammation
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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.
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