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

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.

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

“…Direct IF microscopy for the detection of rabbit IgG and murine C3 in experimental EBA was performed on 6-mm cryosections, as described, using goat anti-rabbit IgG (Dako) and goat anti-murine C3 (MP Biomedicals, Kaysersberg, France), both labeled with FITC. IF microscopy on cultured HUVECs was performed as reported (21,22). In brief, cells were fixed in 220˚C cold methanol for 5 min and washed carefully with PBS before blocking with 5% FCS in PBS for 1 h. Anti-VCAM Ab (clone STA; Immunotools, Friesoythe, Germany), anti-ICAM Ab (clone 15.2; FITC-labeled; Immunotools), and anti-E-selectin Ab (clone 1-2B6; PE-labeled; Abs-online, Aachen, Germany) were diluted in PBS containing 2.5% FCS and incubated overnight before washing with PBS.…”

Dimethylfumarate Impairs Neutrophil Functions

“…Different modes of action of fumaric acid derivatives have been described, including modulation of cytokine production, lymphocyte apoptosis, lymphocyte as well as endothelial lar redox-systems (Vandermeeren et al, 1997, Ghoreschi and Rocken, 2004, Mrowietz and Asadullah, 2005, Rubant et al, 2008, Wallbrecht et al, 2011, Ghoreschi et al, 2011, Mrowietz and Asadullah, 2005, Milenkovic et al, 2008, Treumer et al, 2003. However, only a few studies have addressed the role of fumaric acid derivatives, namely dimethylfumarate (DMF) and its main metabolites methylhydrogenfumarate (MHF) and monomethylfumarate (MMF), on human monocytes and neutrophils after activation.…”

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

“…Data have been published regarding the effects of FAEs (including MMF) on endothelial as well as immune cells; however, little is known about their effects on keratinocytes (Nibbering et al, 1993;Thio et al, 1994;Litjens et al, 2004b;Wallbrecht et al, 2011;Dehmel et al, 2014). Thus, MMF has known effects on immune cells, such as dendritic cells and granulocytes, which could possibly account in part for its antipsoriatic actions (Nibbering et al, 1993;Litjens et al, 2004b).…”