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

Fürst, Robert; Schroeder, Timm; Eilken, Hanna M.; Bubik, Martin F.; Kiemer, Alexandra K.; Zahler, Stefan and Vollmar, Angelika M. (2007): MAPK phosphatase-1 represents a novel antiinflammatory target of glucocorticoids in the human endothelium. In: The FASEB journal, Vol. 21, No. 1: pp. 74-80

Abstract

Glucocorticoids are well-established anti- inflammatory drugs thought to mainly act by inhibition of proinflammatory transcription factors like NF-κB. In recent years, however, transcription factorindependent 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-α-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-κB. Here, we communicate that Dex at low concentrations (1–100 nM) markedly attenuates E-selectin expression without affecting NF-κB. Importantly, Dex is able to increase the expression of MKP-1, which causes an inactivation of TNF-α-induced p38 MAPK and mediates inhibition of E-selectin expression. In endothelial MKP-1ˉ/ˉ cells differentiated from MKP-1ˉ/ˉ embryonic stem cells and in MKP-1-silenced human endothelial cells, Dex did not inhibit TNF-α-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 antiinflammatory drug target.

• Item Type: Journal article
• Form of publication: Publisher's Version
• Keywords: inflammation
• Faculties: Chemistry and Pharmacy
• Subjects: 500 Science > 540 Chemistry
• ISSN: 0892-6638
• Language: English