Dimethylfumarate is an inhibitor of cytokine-induced nuclear translocation of NF-kappa B1, but not RelA in normal human dermal fibroblast cells.
We 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-alpha- or interleukin-1 alpha-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 I kappa B alpha, beta and epsilon proteins: their cytokine-induced degradation and resynthesis is only slowed down, an effect most prominently observed for I kappa B beta. 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 kappa B1/p50 nuclear accumulation was specifically inhibited by dimethylfumarate. This inhibitory effect on nuclear factor kappa B1 nuclear localization in normal human dermal fibroblasts proved sufficient to inhibit nuclear factor kappa B1-RelA binding to nuclear factor kappa B consensus oligonucleotides in DNA binding assays. Likewise, cytokine-induced activation of a pNF kappa B::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 kappa B1 leads to changes in the nuclear factor kappa B1-RelA nuclear balance and inhibition of cytokine-induced adhesion molecule expression in normal human dermal fibroblasts.
Vandermeeren
M
M
Janssen Research Foundation, Beerse, Belgium. mvanderm@janbe.jnj.com
Janssens
S
S
Wouters
H
H
Borghmans
I
I
Borgers
M
M
Beyaert
R
R
Geysen
J
J
D021581:Active Transport, Cell Nucleus; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003879:Dermatologic Agents / Q000494:pharmacology*; D000069462:Dimethyl Fumarate; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology* / Q000187:drug effects
D016207:Cytokines; D003879:Dermatologic Agents; D005650:Fumarates; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D000069462:Dimethyl Fumarate