Dimethylfumarate is a potent inducer of apoptosis in human T cells.
Fumaric acid esters (FAE) have been used for the systemic treatment of psoriasis in Germany for almost 50 years. Recently, it has been shown that dimethylfumarate (DMF) as the main ingredient of the marketed FAE mixture is a potent inhibitor of the nuclear transcription factor NF-kappaB. DMF was also shown to induce apoptosis in various cells. Because T cells play a crucial role in psoriasis pathogenesis, we asked whether DMF and its main metabolite methylhydrogenfumarate (MHF) were able to induce apoptosis in these cells. Purified human T cells were treated with DMF and MHF (1-20 microg/mL) and stimulated with interleukin 2, anti-CD3 antibodies or both for 48 h, and apoptosis was subsequently determined by the expression of Apo2.7 as well as by terminal deoxynucleotide transferase nick end labeling. The expression of antiapoptotic protein Bcl-2 was simultaneously determined. The results showed a dose-and-time dependent up-regulation of Apo2.7 expression and DNA fragmentation by DMF preferable in stimulated T cells. MHF and the solvent dimethyl sulfoxide were without effect. DMF, but not MHF, led to a concentration-dependent decrease of Bcl-2 expression in interleukin-2-stimulated T cells. The data provide evidence that the effect of FAE treatment of psoriasis may at least in part be due to induction of apoptosis in activated T cells.
Treumer
Felix
F
Department of Dermatology, University of Kiel, Kiel, Germany.
Zhu
Kejian
K
Gläser
Regine
R
Mrowietz
Ulrich
U
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003879:Dermatologic Agents / Q000494:pharmacology*; D000069462:Dimethyl Fumarate; D005434:Flow Cytometry / Q000379:methods; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects*
D000970:Antineoplastic Agents; D003879:Dermatologic Agents; D005650:Fumarates; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D000069462:Dimethyl Fumarate