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Int. J. Mol. Sci. 2015, 16(8), 19086-19095; doi:10.3390/ijms160819086

Fumaric Acid Esters Do Not Reduce Inflammatory NF-κB/p65 Nuclear Translocation, ICAM-1 Expression and T-Cell Adhesiveness of Human Brain Microvascular Endothelial Cells

Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, Würzburg 97080, Germany
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Academic Editor: Sven Meuth
Received: 1 June 2015 / Revised: 31 July 2015 / Accepted: 10 August 2015 / Published: 13 August 2015
(This article belongs to the Special Issue Advances in Multiple Sclerosis)
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Abstract

Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 µM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells. View Full-Text
Keywords: blood-brain barrier; endothelial cells; multiple sclerosis; dimethyl fumarate; monomethyl fumarate; cell adhesion; NF-κB; p38 mitogen-activated protein kinase blood-brain barrier; endothelial cells; multiple sclerosis; dimethyl fumarate; monomethyl fumarate; cell adhesion; NF-κB; p38 mitogen-activated protein kinase
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Haarmann, A.; Nehen, M.; Deiß, A.; Buttmann, M. Fumaric Acid Esters Do Not Reduce Inflammatory NF-κB/p65 Nuclear Translocation, ICAM-1 Expression and T-Cell Adhesiveness of Human Brain Microvascular Endothelial Cells. Int. J. Mol. Sci. 2015, 16, 19086-19095.

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