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

Robert Fürst^*, Timm Schroeder, Hanna M. Eilken, Martin F. Bubik^*, Alexandra K. Kiemer, Stefan Zahler^* and Angelika M. Vollmar^*

^* Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany;

GSF – National Research Center for Environment and Health, Institute of Stem Cell Research, Neuherberg, Germany; and

Institute of Pharmaceutical Biology, Saarland University, Saarbrücken, Germany

¹Correspondence: University of Munich, Department of Pharmacy, Pharmaceutical Biology, Butenandtstr. 5–13, 81377 Munich, Germany. E-mail: robert.fuerst{at}cup.uni-muenchen.de

Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition of proinflammatory transcription factors like NF-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--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-B. Here, we communicate that Dex at low concentrations (1–100 nM) markedly attenuates E-selectin expression without affecting NF-B. Importantly, Dex is able to increase the expression of MKP-1, which causes an inactivation of TNF--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--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.—Fürst, R., Schroeder, T., Eilken, H. M., Bubik, M. F., Kiemer, A. K., Stefan Zahler, S., Vollmar, A. M. MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium

Key Words: inflammation

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