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.
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.
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, Würzburg 97080, Germany. haarmann_a@ukw.de.
Axel
A
Haarmann
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, Würzburg 97080, Germany. mathias.nehen@stud-mail.uni-wuerzburg.de.
Mathias
M
Nehen
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, Würzburg 97080, Germany. deiss_a@ukw.de.
Annika
A
Deiß
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, Würzburg 97080, Germany. m.buttmann@ukw.de.
Mathias
M
Buttmann
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D005650:Fumarates / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D008298:Maleates / Q000494:pharmacology*; D055806:Microvessels / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051996:Transcription Factor RelA / Q000032:analysis / Q000276:immunology*
D005650:Fumarates; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D008298:Maleates; D051996:Transcription Factor RelA; C073341:citraconic acid; D018799:Intercellular Adhesion Molecule-1; D000069462:Dimethyl Fumarate
NF-κB; blood-brain barrier; cell adhesion; dimethyl fumarate; endothelial cells; monomethyl fumarate; multiple sclerosis; p38 mitogen-activated protein kinase