Dimethylfumarate induces apoptosis in human mast cells
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Anja Förster1, Liane M Preussner, Jens M Seeger
1Department of Dermatology, University of Cologne, Cologne, Germany.
Abstract:
Mast cells modulate autoimmune diseases such as psoriasis and multiple sclerosis. Fumaric acid esters (FAEs) are widely used for the treatment of psoriasis, and dimethylfumarate (DMF) has recently been approved for multiple sclerosis. In this study, we analysed the cytotoxic effect of FAEs on human mast cells. Specifically, cell death was analysed in the human mast cell line HMC-1 and in primary cord blood-derived mast cells (CBMCs) after incubation with fumaric acid (FA), monomethylfumarate (MMF), DMF and calcium bis(monomethylfumarate) (Ca-MF). Our data show that only DMF potently induces apoptotic cell death in HMC-1 cells and CBMCs. DMF-mediated apoptosis was associated with increased expression of Bax and Bak and activation of caspase-9 and caspase-6. Interestingly, DMF also enhanced the sensitivity of CBMCs towards TRAIL- and dexamethasone-induced apoptosis. These findings demonstrate for the first time that DMF induces apoptosis of human mast cells, primarily via the mitochondrial apoptotic pathway. Our study contributes to the understanding of the beneficial effects of FAEs in autoimmune diseases and provides a rationale for exploiting FAEs for other diseases associated with mast cells.
Insights
Dimethylfumarate (DMF) induces programmed cell death in human mast cells, offering new insights into treating autoimmune diseases like psoriasis and multiple sclerosis. This research explains how DMF impacts mast cells, aiding future therapeutic strategies.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Mast cells play a significant role in modulating autoimmune conditions such as psoriasis and multiple sclerosis.
- Fumaric acid esters (FAEs) are established treatments for psoriasis, with dimethylfumarate (DMF) recently gaining approval for multiple sclerosis therapy.
Purpose of the Study:
- To investigate the cytotoxic effects of Fumaric Acid Esters (FAEs) on human mast cells.
- To elucidate the specific mechanisms by which DMF induces cell death in mast cells.
Main Methods:
- Analysis of cell death in the HMC-1 human mast cell line and primary cord blood-derived mast cells (CBMCs).
- Incubation of mast cells with fumaric acid (FA), monomethylfumarate (MMF), dimethylfumarate (DMF), and calcium bis(monomethylfumarate) (Ca-MF).
- Assessment of apoptotic markers, including Bax and Bak expression, and caspase-9 and caspase-6 activation.
Main Results:
- Dimethylfumarate (DMF) was identified as the sole FAE that potently induced apoptotic cell death in both HMC-1 cells and CBMCs.
- DMF-induced apoptosis involved upregulation of Bax and Bak, and activation of caspase-9 and caspase-6, indicating a mitochondrial pathway.
- DMF enhanced the susceptibility of CBMCs to apoptosis induced by TRAIL and dexamethasone.
Conclusions:
- Dimethylfumarate (DMF) induces apoptosis in human mast cells, primarily through the mitochondrial apoptotic pathway.
- These findings provide a mechanistic understanding for the therapeutic benefits of FAEs in autoimmune diseases.
- The study suggests potential for FAEs in treating other mast cell-associated disorders.
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