Dimethylfumarate reduces leukocyte rolling in vivo through modulation of adhesion molecule expression.
Esters of fumaric acid have a long tradition in the treatment of psoriasis. Dimethylfumarate (DMF) is perceived as the main active substance. However, the molecular mechanisms of DMF action are not completely understood. Here, we investigate the effects of DMF on lymphocyte adhesion molecule expression in vitro and interactions with endothelial cells in vivo. DMF dose-dependently reduced superantigen-induced expression of CD25, human leukocyte antigen-DR, and cutaneous lymphocyte antigen by 27, 22, and 48% on CD3-positive cells, respectively. No change was observed for CD54, VLA-4, and P-selectin glycoprotein ligand-1. An enhancement of CD69 expression was noted (22%). DMF led to a significant reduction in binding of human peripheral blood mononuclear cells (PBMCs) to E-selectin (72%), P-selectin (36%), and vascular cell adhesion molecule-1 (33%) in vitro. Intravital microscopy of PBMCs in ear vasculature of wild-type and knockout mice showed that rolling was mainly P-selectin-dependent and could be reduced by 61% through DMF incubation. We provide early evidence that DMF affects adhesion molecule expression on human leukocytes and their rolling behavior in vivo, indicating that DMF directly affects the initial step of leukocyte extravasation.
Rubant
Simone A
SA
Department of Dermatology, Clinic of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. s.rubant@em.uni-frankfurt.de
Ludwig
Ralf J
RJ
Diehl
Sandra
S
Hardt
Katja
K
Kaufmann
Roland
R
Pfeilschifter
Josef M
JM
Boehncke
Wolf-Henning
WH
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects* / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D036904:Leukocyte Rolling / Q000187:drug effects* / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D018089:Superantigens / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D014699:Venules / Q000166:cytology
D001427:Bacterial Toxins; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D004768:Enterotoxins; D005650:Fumarates; D007166:Immunosuppressive Agents; D019007:P-Selectin; D018089:Superantigens; D019010:Vascular Cell Adhesion Molecule-1; C030107:enterotoxin F, Staphylococcal; D000069462:Dimethyl Fumarate