The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1.
The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1.
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DOI：
10.1042/an20100033
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发表时间：
2011-04-07
期刊：
影响因子：
4.7
通讯作者：
Feinstein DL
中科院分区：
文献类型：
--
作者：
Lin SX;Lisi L;Dello Russo C;Polak PE;Sharp A;Weinberg G;Kalinin S;Feinstein DL
DMF（富马酸二甲酯）在多种细胞类型中发挥抗炎和促代谢作用，目前正在评价一种制剂（BG-12）在多发性硬化症患者中的单药治疗效果。DMF可改变谷胱甘肽（GSH）水平，从而诱导抗炎蛋白HO-1（血红素加氧酶-1）的表达。在原代星形胶质细胞和C6神经胶质瘤细胞中，BG-12剂量依赖性地抑制LI [1 μg/ml LPS（脂多糖）加20单位/ml IFNγ（干扰素γ）]或促炎细胞因子混合物诱导的亚硝酸盐产生，在C6细胞中具有更大的疗效。BG-12降低了两种细胞类型中NOS 2（一氧化氮合酶2）mRNA水平和NOS 2启动子的激活，降低了NF-κB（核因子κB）p65亚基的核水平，并减弱了IκBα（抑制性κBα）的丢失，但在星形胶质细胞中的作用更大。在星形胶质细胞中，LI降低GSHr（GSH还原酶）和GCL（c-谷氨酰半胱氨酸合成酶）的mRNA水平，并轻微抑制GSH（GSH合成酶）mRNA。与BG-12的共同治疗防止了这些降低和升高的水平高于对照值。相反，LI降低C6细胞中的GSHp（GSH过氧化物酶）和GCL，BG-12对这些水平没有影响。BG-12增加了星形胶质细胞中Nrf 2（核因子-红细胞2 p45亚基相关因子2）的核水平，这是一种GSH相关酶的诱导剂，但不包括C6细胞。在星形胶质细胞中，GSH在BG-12作用2 h时降低，24 h时升高。先前使用丁硫氨酸-亚砜亚胺耗尽GSH增加BG-12还原亚硝酸盐的能力。在星形胶质细胞中，BG-12增加HO-1 mRNA水平，对亚硝酸盐水平的影响被HO-1抑制剂阻断。这些结果表明，BG-12抑制星形胶质细胞和C6胶质瘤细胞中的炎症活化，但具有不同的机制，对GSH的不同依赖性和对转录因子活化的不同影响。
DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 μg/ml plus IFNγ (interferon γ) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-κB (nuclear factor κB) p65 subunit and attenuated loss of IκBα (inhibitory κBα) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation.