title: Monomethylfumarate reduces in vitro migration of mononuclear cells.
abstract: Migration of immunocompetent cells into the central nervous system represents a key event in the immunopathogenesis of multiple sclerosis (MS). Fumaric acid esters have recently been approved for patients with MS. Their mode of action is not fully understood so far. We analyzed the effect of monomethylfumarate (MMF), the immediate metabolite of dimethylfumarate, on migration of lymphocytes and macrophages. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with MS and healthy donors. PBMCs were treated with MMF in vitro and their migratory capacity was studied in a Boyden chamber assay. In addition, expression of matrix metalloproteinases (MMPs), chemokine receptors, adhesion molecules, and molecules of the oxidative stress cascade was assessed. MMF decreased the migratory capacity of T lymphocytes, but not of macrophages. Lymphocytes as well as macrophages responded to MMF by the upregulation of oxidative stress molecules; however, no effect was seen on the expression of MMPs, chemokine receptors, and adhesion molecules. There was no difference in comparison with cells from healthy controls. MMF reduces the migratory activity of lymphocytes most likely by changing their activational state. This points to a potential novel mode of action differentiating this drug from other available immunotherapies.
authors: Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
authors: T
authors: T
authors: Dehmel
authors: M
authors: M
authors: Döbert
authors: S
authors: S
authors: Pankratz
authors: V I
authors: VI
authors: Leussink
authors: H-P
authors: HP
authors: Hartung
authors: H
authors: H
authors: Wiendl
authors: B C
authors: BC
authors: Kieseier
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005650:Fumarates / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000097:blood*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D005650:Fumarates; D008298:Maleates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C073341:citraconic acid; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005721:Glutamate-Cysteine Ligase