Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells.
Fumaric acid esters, mainly dimethylfumarate (DMF), have been successfully used to treat psoriasis. Based on previous observations that DMF inhibited expression of several TNF-induced genes in endothelial cells, we wished to explore the molecular basis of DMF function in greater detail. In first experiments we analyzed DMF effects on tissue factor expression in human endothelial cells in culture, because tissue factor is expressed by two independent sets of transcription factors, by NF-kappa B via TNF and by early gene response-1 transcription factor via vascular endothelial growth factor (VEGF). We show that DMF inhibits TNF-induced tissue factor mRNA and protein expression as well as TNF-induced DNA binding of NF-kappa B proteins, but not VEGF-induced tissue factor protein, mRNA expression, or VEGF-induced early gene response-1 transcription factor/DNA binding. To determine where DMF interferes with the TNF/NF-kappa B signaling cascade, we next analyzed DMF effects on I kappa B and on the subcellular distribution of NF-kappa B. DMF does not inhibit TNF-induced I kappa B alpha phosphorylation and I kappa B degradation; thus, NF-kappa B is properly released from I kappa B complexes even in the presence of DMF. Importantly, DMF inhibits the TNF-induced nuclear entry of NF-kappa B proteins, and this effect appears selective for NF-kappa B after the release from I kappa B, because the constitutive shuttling of inactive NF-kappa B/I kappa B complexes into and out from the nucleus is not blocked by DMF. Moreover, DMF does not block NF-kappa B/DNA binding. In conclusion, DMF appears to selectively prevent the nuclear entry of activated NF-kappa B, and this may be the basis of its beneficial effect in psoriasis.
Loewe
Robert
R
Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Vienna, Austria.
Holnthoner
Wolfgang
W
Gröger
Marion
M
Pillinger
Manuela
M
Gruber
Florian
F
Mechtcheriakova
Diana
D
Hofer
Erhard
E
Wolff
Klaus
K
Petzelbauer
Peter
P
D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D005231:Fatty Acids, Unsaturated; D005650:Fumarates; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D000069462:Dimethyl Fumarate; C038753:leptomycin B