Dimethylfumarate specifically inhibits the mitogen and stress-activated kinases 1 and 2 (MSK1/2): possible role for its anti-psoriatic effect.
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.
Gesser
Borbala
B
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.
Johansen
Claus
C
Rasmussen
Mads K
MK
Funding
Anne T
AT
Otkjaer
Kristian
K
Kjellerup
Rasmus B
RB
Kragballe
Knud
K
Iversen
Lars
L
D001665:Binding Sites; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011565:Psoriasis / Q000188:drug therapy*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D005650:Fumarates; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D007378:Interleukins; D016328:NF-kappa B; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D000069462:Dimethyl Fumarate; C422042:interleukin 20