Dimethylfumarate induces apoptosis in human mast cells
Dimethylfumarate induces apoptosis in human mast cells
复制标题
DOI：
10.1111/exd.12247
复制
发表时间：
2013-11-01
影响因子：
3.6
通讯作者：
Hartmann, Karin
中科院分区：
文献类型：
--
作者：
Foerster, Anja;Preussner, Liane M.;Hartmann, Karin
肥大细胞调节自身免疫性疾病，如牛皮癣和多发性硬化症。富马酸酯（FAE）广泛用于治疗银屑病，富马酸二甲酯（DMF）最近已被批准用于多发性硬化症。在这项研究中，我们分析了FAE对人肥大细胞的细胞毒性作用。具体而言，在与富马酸（FA）、富马酸单甲酯（MMF）、DMF和双（富马酸单甲酯）钙（Ca-MF）孵育后，分析了人肥大细胞系HMC-1和原代脐带血来源的肥大细胞（CBMC）中的细胞死亡。我们的数据表明，只有DMF在HMC-1细胞和CBMC中有效诱导凋亡性细胞死亡。DMF介导的细胞凋亡与Bax和巴克的表达增加以及caspase-9和caspase-6的激活有关。有趣的是，DMF还增强了CBMCs对TRAIL和地塞米松诱导的细胞凋亡的敏感性。这些发现首次证明DMF主要通过线粒体凋亡途径诱导人肥大细胞凋亡。我们的研究有助于了解FAE在自身免疫性疾病中的有益作用，并为利用FAE治疗与肥大细胞相关的其他疾病提供了理论基础。
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.