Dimethylfumarate inhibits nuclear binding of nuclear factor kappaB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein beta in activated human T cells.
BACKGROUND
Psoriasis is a chronic inflammatory skin disorder in which T-cell-mediated immune responses are thought to play a prominent role. Fumaric acid esters (FAEs) have proved to be an effective systemic treatment for psoriasis. The FAE dimethylfumarate (DMF) strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Additionally, it has been demonstrated that the nuclear translocation of the activated transcription factor nuclear factor kappaB (NF-kappaB) is inhibited in human endothelial cells and fibroblasts activated with tumour necrosis factor-alpha. The NF-kappaB pathway plays a major role in regulating inflammatory cytokine production as well as in cell differentiation and apoptosis. T-cell survival is also dependent on the activation of NF-kappaB and it has been demonstrated in vitro that DMF is an inducer of apoptosis in human T cells. The influence of FAEs on the expression of nuclear transcription factors in T cells has not yet been investigated.


OBJECTIVE
The effects of DMF and its main metabolite, methylhydrogenfumarate (MHF), were assessed on the nuclear binding of NF-kappaB, nuclear factor of activated T cells (NF-AT) and CCAAT/enhancer binding protein beta (C/EBPbeta) in purified human T cells.


METHODS
To examine the effect of DMF and MHF on the nuclear binding of NF-kappaB, NF-AT and C/EBPbeta in human T cells and fibroblasts, an enzyme-linked immunosorbent assay (ELISA) was used. The binding activity of these transcription factors was measured by its absorbance in an ELISA plate reader at 450 nm. Conspicuous results were confirmed by performing electrophoretic mobility shift assays.


RESULTS
DMF inhibited nuclear binding of NF-kappaB1, but not of NF-AT or C/EBPbeta, in purified human T cells. No effect of MHF on any of these transcription factors could be seen. To verify our results, we used the same assay to show the inhibitory effect on the nuclear binding of NF-kappaB1 in human fibroblasts (as previously published).


CONCLUSIONS
The results of this study provide evidence for a specific effect of DMF on NF-kappaB. The data support previous results where NF-kappaB-dependent mediators and surface molecules were suppressed by DMF, but not those activated by other nuclear transcription factors.
Gerdes
S
S
Psoriasis Center at the Department of Dermatology, University of Kiel, Schittenhelmstr 7, Kiel, Germany. sgerdes@dermatology.uni-kiel.de
Shakery
K
K
Mrowietz
U
U
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000187:drug effects* / Q000378:metabolism; D000069462:Dimethyl Fumarate; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects
D022782:CCAAT-Enhancer-Binding Protein-beta; D005650:Fumarates; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C509058:monomethyl fumarate; D000069462:Dimethyl Fumarate