Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.
Fumaric acid esters are thought to improve psoriasis by altering leukocyte, keratinocyte, and/or endothelial functions. To determine specificity, kinetics, and molecular mechanisms of different fumaric acid esters in their ability to inhibit endothelial cell activation, we analyzed CD62E and CD54 expression in endothelial cells in vivo and in vitro. In lesional skin of psoriatic patients, oral fumaric acid ester treatment resulted in a marked reduction of CD62E but not CD54 expression on dermal microvessels. Using human umbilical vein endothelial cells, dimethylfumarate almost completely inhibited tumor-necrosis-factor-induced CD62E, but not CD54 expression at concentrations < or = 70 microM, mimicking the situation in vivo. A 60 min dimethylfumarate preincubation was sufficient to block tumor-necrosis-factor-induced CD62E expression for up to 24 h. In contrast, equimolar concentrations of methylhydrogenfumarate, the hydrolysis product of dimethylfumarate, did not suppress tumor-necrosis-factor-induced CD62E expression. Likewise, all fumaric acid esters other than dimethylfumarate were ineffective. Using CD62E, NF-kappa B, or AP-1-responsive promoter constructs, dimethylfumarate inhibited tumor-necrosis-factor-induced activation of the CD62E and the NF-kappa B but not the AP-1 promoter construct. In summary, at a dose range < or = 70 microM, dimethylfumarate appeared to be a specific inhibitor of CD62E expression in an NF-kappa B-dependent manner.
Loewe
R
R
Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Vienna, Austria.
Pillinger
M
M
de Martin
R
R
Mrowietz
U
U
Gröger
M
M
Holnthoner
W
W
Wolff
K
K
Wiegrebe
W
W
Jirovsky
D
D
Petzelbauer
P
P
D002196:Capillaries / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003879:Dermatologic Agents / Q000494:pharmacology*; D000069462:Dimethyl Fumarate; D019040:E-Selectin / Q000032:analysis / Q000235:genetics*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D005650:Fumarates / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D011565:Psoriasis / Q000188:drug therapy / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000098:blood supply; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology
D003879:Dermatologic Agents; D019040:E-Selectin; D005650:Fumarates; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000069462:Dimethyl Fumarate