Dimethylfumarate specifically inhibits the mitogen and stress-activated kinases 1 and 2 (MSK1/2): possible role for its anti-psoriatic effect

J Invest Dermatol. 2007 Sep;127(9):2129-37. doi: 10.1038/sj.jid.5700859. Epub 2007 May 10.


The p38 mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the activity of different transcriptions factors including NF-kappaB, 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-1beta 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-1beta, whereas MHF and FA had no effect. In addition, DMF decreased phosphorylation of NF-kappaB/p65 (Ser276), which is known to be transactivated by MSK1. Furthermore, incubation with DMF before stimulation with IL-1beta resulted in a significant decrease in NF-kappaB binding to the IL-8 kappaB and the IL-20 kappaB-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-kappaB-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cells, Cultured
  • Dimethyl Fumarate
  • Enzyme Inhibitors / pharmacology*
  • Fumarates / pharmacology*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Interleukin-1beta / metabolism
  • Interleukins / metabolism
  • Keratinocytes / metabolism
  • NF-kappa B / metabolism
  • Oxidation-Reduction
  • Phosphorylation
  • Psoriasis / drug therapy*
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*


  • Enzyme Inhibitors
  • Fumarates
  • Immunosuppressive Agents
  • Interleukin-1beta
  • Interleukins
  • NF-kappa B
  • RPS6KA4 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Dimethyl Fumarate
  • interleukin 20