Original Article
Subject Category: Cell Biology
Journal of Investigative Dermatology (2007) 127, 2129–2137; doi:10.1038/sj.jid.5700859; published online 10 May 2007
Dimethylfumarate Specifically Inhibits the Mitogen and Stress-Activated Kinases 1 and 2 (MSK1/2): Possible Role for its Anti-Psoriatic Effect
Borbala Gesser1, Claus Johansen1, Mads K Rasmussen1, Anne T Funding1, Kristian Otkjaer1, Rasmus B Kjellerup1, Knud Kragballe1 and Lars Iversen1
1Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
Correspondence: Dr Lars Iversen, Department of Dermatology, Aarhus University Hospital, P. P. Orumsgade 11, DK-8000 Aarhus C, Denmark. E-mail: lars.iversen@ki.au.dk
Received 7 December 2006; Revised 23 February 2007; Accepted 6 March 2007; Published online 10 May 2007.
Abstract
The p38 mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the activity of different transcriptions factors including NF-
B, is activated in lesional psoriatic skin. The purpose of this study was to investigate the effect of fumaric acid esters (FAEs) on the p38 MAPK and the downstream kinases mitogen- and stress-activated protein kinase (MSK)1 and 2 in cultured human keratinocytes. Cell cultures were incubated with dimethylfumarate (DMF), methylhydrogenfumarate (MHF), or fumaric acid (FA) and then stimulated with IL-1
before kinase activation was determined by Western blotting. A significant inhibition of both MSK1 and 2 activations was seen after preincubation with DMF and stimulation with IL-1
, whereas MHF and FA had no effect. In addition, DMF decreased phosphorylation of NF-
B/p65 (Ser276), which is known to be transactivated by MSK1. Furthermore, incubation with DMF before stimulation with IL-1
resulted in a significant decrease in NF-
B binding to the IL-8
B and the IL-20
B-binding sites as well as a subsequent decrease in IL-8 and IL-20 mRNA expression. Our results suggest that DMF specifically inhibits MSK1 and 2 activations and subsequently inhibits NF-
B-induced gene–transcriptions, which are believed to be important in the pathogenesis of psoriasis. These effects of DMF explain the anti-psoriatic effect of FAEs.
Abbreviations:
ATF1, activation transcription factor 1; CREB, cAMP-response element-binding protein; DMF, dimethylfumarate; ERK, extracellular signal-regulated kinase; FA, fumaric acid; FAE, fumaric acid ester; MAPK, mitogen-activated protein kinase; MHF, methylhydrogenfumarate; MK2, MAPK-activated protein kinase 2; MSK1 and 2, mitogen- and stress-activated protein kinase 1 and 2
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