MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium.
Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition of proinflammatory transcription factors like NF-kappaB. 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-kappaB. Here, we communicate that Dex at low concentrations (1-100 nM) markedly attenuates E-selectin expression without affecting NF-kappaB. 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.
Fürst
Robert
R
University of Munich, Department of Pharmacy, Pharmaceutical Biology, Butenandtstr. 5-13, 81377 Munich, Germany. robert.fuerst@cup.uni-muenchen.de
Schroeder
Timm
T
Eilken
Hanna M
HM
Bubik
Martin F
MF
Kiemer
Alexandra K
AK
Zahler
Stefan
S
Vollmar
Angelika M
AM
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D004790:Enzyme Induction; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018797:Cell Cycle Proteins; D017931:DNA Primers; D019040:E-Selectin; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases