Dimethylfumarate is an Inhibitor of Cytokine-Induced Nuclear Translocation of NF-κB1, But Not RelA in Normal Human Dermal Fibroblast Cells

Vandermeeren, Marc; Janssens, Sophie; Wouters, Hilde; Borghmans, Inge; Borgers, Marcel; Beyaert, Rudi; Geysen, Johan
January 2001
Journal of Investigative Dermatology;Jan2001, Vol. 116 Issue 1, p124
Academic Journal
SummaryWe previously demonstrated that the oral antipsoriatic dimethylfumarate is an inhibitor of cytokine-induced adhesion molecule expression in endothelial HUVEC cells. We now report the inhibitory effect of dimethylfumarate on tumor-necrosis-factor-α- or interleukin-1α-induced intercellular adhesion molecule 1 expression in normal human dermal fibroblasts. Western blots of normal human dermal fibroblast cytoplasmic extracts showed that dimethylfumarate has minor effects on the IκBα, β and ε proteins: their cytokine-induced degradation and resynthesis is only slowed down, an effect most prominently observed for IκBβ. No inhibitory effect of dimethylfumarate was observed on cytokine-induced RelA/p65 or c-Rel accumulation in nuclear extracts of cytokine-treated normal human dermal fibroblast cells. In contrast, cytokine-induced nuclear factor κB1/p50 nuclear accumulation was specifically inhibited by dimethylfumarate. This inhibitory effect on nuclear factor κB1 nuclear localization in normal human dermal fibroblasts proved sufficient to inhibit nuclear factor κB1-RelA binding to nuclear factor κB consensus oligonucleotides in DNA binding assays. Likewise, cytokine-induced activation of a pNFκB::luciferase reporter construct in transiently transfected normal human dermal fibroblasts was inhibited by dimethylfumarate. The observations support a mechanistic model for the oral antipsoriatic dimethylfumarate in which lowering of nuclear factor κB1 leads to changes in the nuclear factor κB1-RelA nuclear balance and inhibition of cytokine-induced adhesion molecule expression in normal human dermal fibroblasts.


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