Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions

Exp Dermatol. 2011 Dec;20(12):980-5. doi: 10.1111/j.1600-0625.2011.01376.x. Epub 2011 Oct 13.

Abstract

Although fumaric acid esters (FAE) have a decade-long firm place in the therapeutic armamentarium for psoriasis, their pleiotropic mode of action is not yet fully understood. While most previous studies have focused on the effects of FAE on leucocytes, we have addressed their activity on macro- and microvascular endothelial cells. As detected both on mRNA and protein levels, dimethylfumarate effected a profound reduction of TNFα-induced expression of E-selectin (CD62E), ICAM-1 (CD54) and VCAM-1 (CD106) on two different endothelial cell populations in a concentration-dependent manner. This reduction of several endothelial adhesion molecules was accompanied by a dramatic diminution of both rolling and firm adhesive interactions between endothelial cells and lymphocytes in a dynamic flow chamber system. Dimethylfumarate, at a concentration of 50 μm, reduced lymphocyte rolling on endothelial cells by 85.9% (P<0.001 compared to untreated controls), and it diminished the number of adherent cells by 88% (P<0.001). In contrast, monomethylfumarate (MMF) influenced neither surface expression of adhesion molecules nor interactions between endothelial cells and lymphocytes. These observations demonstrate that endothelial cells, in addition to the known effects on leucocytes, undergo profound functional changes in response to dimethylfumarate. These changes are accompanied by severely impaired dynamic interactions with lymphocytes, which constitute the critical initial step of leucocyte recruitment to inflamed tissues in psoriasis and other TNF-related inflammatory disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line, Transformed
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Dimethyl Fumarate
  • Down-Regulation / genetics*
  • E-Selectin / genetics
  • E-Selectin / metabolism
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Fumarates / pharmacology*
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leukocyte Rolling / drug effects*
  • Leukocyte Rolling / physiology
  • Lymphocytes / cytology*
  • Maleates / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • Cell Adhesion Molecules
  • E-Selectin
  • Fumarates
  • Maleates
  • Tumor Necrosis Factor-alpha
  • VEGFA protein, human
  • Vascular Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • citraconic acid
  • Intercellular Adhesion Molecule-1
  • Dimethyl Fumarate