title: Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells.
abstract: BACKGROUND
  Inflammation, angiogenesis and oxidative stress have been implicated in the pathogenesis of various vascular diseases. Recent evidence suggests that dimethylfumarate (DMF), an antiposriatic and anti-multiple sclerosis agent, possesses anti-inflammatory, anti-oxidative and anti-angiogenic properties. Here, we analyze the influence of DMF on TNF-α-induced expression of the important pro-inflammatory and pro-atherogenic chemokine MCP-1 and investigate the underlying mechanisms of this expression.
  
  
  RESULTS
  We analyzed constitutive and TNF-α-induced expression of MCP-1 in human umbilical vascular endothelial cells (HUVEC) +/- DMF treatment via enzyme-linkes immunosorbent assay (ELISA). DMF significantly inhibited the protein expression levels in a time- and concentration-dependent manner. Furthermore, MCP-1 mRNA expression was also reduced in response to DMF, as demonstrated by RT-PCR. Thus, the regulation occurs at the transcriptional level. Interestingly, DMF prolonged the TNF-α-induced p38 and JNK phosphorylation in HUVEC, as demonstrated by Western blot analysis; however, the p38 and JNK inhibitor SB203580 did not affect the DMF-conveyed suppression of TNF-α-induced MCP-1 expression. DMF suppressed the TNF-α-induced nuclear translocation and phosphorylation (Serine 536) of p65 in these cells. These results were additionally approved by p65 luciferase promoter assays. Furthermore, we found that DMF slightly inhibited the early degradation of IκBα. In addition, we verified our results using other important inflammatory cytokines such as CCL-5, PDGF-BB, GM-CSF and IL-6.
  
  
  CONCLUSIONS
  DMF suppresses various TNF-α-induced pro-inflammatory and pro-atherogenic cytokines/chemokines in human endothelial cells. This action is regulated by reduced p65 activity and nuclear translocation, which can be explained in part by the reduced early degradation of IκBα and more important the reduced phosphorylation of p65 at Serine 536. These effects were independent of the p38, PI3K and p42/44 signaling pathways. As a result, DMF might be suitable for treating patients with vascular diseases.
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany ; Department of Cardiology, Gutenberg-University, Mainz, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Gerhardt
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: König
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Doll
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Tsige
authors.initials: T
authors.lastname: Hailemariam-Jahn
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Hrgovic
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Zöller
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kaufmann
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kippenberger
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Meissner
keywords: Dimethylfumarate; MCP-1; TNF-α; p65; ΙκΒα