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Dimethylfumarate Specifically Inhibits the Mitogen and Stress-Activated Kinases 1 and 2 (MSK1/2): Possible Role for its Anti-Psoriatic Effect

2007; Elsevier BV; Volume: 127; Issue: 9 Linguagem: Inglês

10.1038/sj.jid.5700859

1523-1747

Borbala Gesser, Claus Johansen, Mads Kirchheiner Rasmussen, Anne T. Funding, Kristian Otkjær, R.B. Kjellerup, Knud Kragballe, Lars Iversen,

Melanoma and MAPK Pathways

The p38 mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the activity of different transcriptions factors including NF-κB, 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-1β 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-1β, whereas MHF and FA had no effect. In addition, DMF decreased phosphorylation of NF-κB/p65 (Ser276), which is known to be transactivated by MSK1. Furthermore, incubation with DMF before stimulation with IL-1β resulted in a significant decrease in NF-κB binding to the IL-8 κB and the IL-20 κB-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-κB-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. The p38 mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the activity of different transcriptions factors including NF-κB, 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-1β 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-1β, whereas MHF and FA had no effect. In addition, DMF decreased phosphorylation of NF-κB/p65 (Ser276), which is known to be transactivated by MSK1. Furthermore, incubation with DMF before stimulation with IL-1β resulted in a significant decrease in NF-κB binding to the IL-8 κB and the IL-20 κB-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-κB-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. activation transcription factor 1 cAMP-response element-binding protein dimethylfumarate extracellular signal-regulated kinase fumaric acid fumaric acid ester mitogen-activated protein kinase methylhydrogenfumarate MAPK-activated protein kinase 2 mitogen- and stress-activated protein kinase 1 and 2