Rubant Simone A, Ludwig Ralf J, Diehl Sandra, Hardt Katja, Kaufmann Roland, Pfeilschifter Josef M, Boehncke Wolf-Henning
Department of Dermatology, Clinic of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
J Invest Dermatol. 2008 Feb;128(2):326-31. doi: 10.1038/sj.jid.5700996. Epub 2007 Aug 2.
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.
富马酸酯在银屑病治疗方面有着悠久的历史。富马酸二甲酯（DMF）被视为主要活性物质。然而，DMF的作用分子机制尚未完全明确。在此，我们研究了DMF在体外对淋巴细胞黏附分子表达的影响以及在体内与内皮细胞的相互作用。DMF呈剂量依赖性地使超抗原诱导的CD25、人类白细胞抗原-DR和皮肤淋巴细胞抗原在CD3阳性细胞上的表达分别降低27%、22%和48%。CD54、VLA-4和P-选择素糖蛋白配体-1未观察到变化。注意到CD69表达增强（22%）。DMF在体外导致人类外周血单个核细胞（PBMC）与E-选择素（72%）、P-选择素（36%）和血管细胞黏附分子-1（33%）的结合显著减少。对野生型和基因敲除小鼠耳部血管中的PBMC进行活体显微镜观察显示，滚动主要依赖P-选择素，通过DMF孵育可减少61%。我们提供了早期证据表明，DMF影响人类白细胞上黏附分子的表达及其在体内的滚动行为，这表明DMF直接影响白细胞外渗的初始步骤。
