Dimethylfumarate inhibits nuclear binding of nuclear factor κB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein β in activated human T cells.

Autor: Gerdes, S., Shakery, K., Mrowietz, U.
Předmět:
Zdroj: British Journal of Dermatology; May2007, Vol. 156 Issue 5, p838-842, 5p, 1 Graph
Abstrakt: 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 κB (NF- κB) is inhibited in human endothelial cells and fibroblasts activated with tumour necrosis factor- α. The NF- κB 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- κB 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. Objectives The effects of DMF and its main metabolite, methylhydrogenfumarate (MHF), were assessed on the nuclear binding of NF- κB, nuclear factor of activated T cells (NF-AT) and CCAAT/enhancer binding protein β (C/EBP β) in purified human T cells. Methods To examine the effect of DMF and MHF on the nuclear binding of NF- κB, NF-AT and C/EBP β 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- κB1, but not of NF-AT or C/EBP β, 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- κB1 in human fibroblasts (as previously published). Conclusions The results of this study provide evidence for a specific effect of DMF on NF- κB. The data support previous results where NF- κB-dependent mediators and surface molecules were suppressed by DMF, but not those activated by other nuclear transcription factors. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
Externí odkaz: