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.