Iron overload induced by ferric ammonium citrate triggers reactive oxygen species-mediated apoptosis via both extrinsic and intrinsic pathways in human hepatic cells
Iron overload induced by ferric ammonium citrate triggers reactive oxygen species-mediated apoptosis via both extrinsic and intrinsic pathways in human hepatic cells
复制标题
柠檬酸铁铵诱导的铁过载通过人肝细胞的外在和内在途径触发活性氧介导的细胞凋亡
DOI：
10.1177/0960327115597312
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发表时间：
2016-06-01
影响因子：
2.8
通讯作者：
Guan, F.
中科院分区：
文献类型：
--
作者：
Li, S-W;Liu, C-M;Guan, F.
工作背景：肝脏铁超负荷在接受造血细胞移植（HCT）的骨髓增生异常综合征患者中很常见，并可能导致HCT期间和HCT后毒性。为了更好地了解铁超载导致肝损伤的机制，我们研究了柠檬酸铁铵（FAC）诱导的铁超载对人肝细胞株HH 4氧化应激和凋亡信号通路的影响。方法和结果：肝HH 4细胞暴露于FAC以强制铁摄取，并测定细胞反应。与5 mM FAC孵育导致细胞内铁含量以时间依赖性方式增加。高浓度的FAC损害细胞活力和活性氧（ROS）的水平增加，并添加抗氧化剂，如谷胱甘肽或N-乙酰半胱氨酸显着减少FAC诱导的细胞内ROS的产生。FAC过负荷可显著增加活化B-α抑制因子、p38丝裂原活化蛋白激酶（MAPK）和活化B细胞核因子κ轻链增强子（NF-κB）p65的磷酸化水平，并促进NF-κB p65的核转位。在铁处理的HH 4细胞中通过小干扰RNA敲低Fas和Bid表达导致细胞活力恢复。结论：我们报道了FAC处理能够通过ROS激活的p38 MAPK和NF-κB途径诱导外源性死亡受体和内源性线粒体信号通路介导的HH 4细胞凋亡。
Background: Hepatic iron overload is common in patients with myelodysplastic syndromes undergoing hematopoietic cell transplantation (HCT) and may predispose to peri- and post-HCT toxicity. To better understand the mechanisms of iron overload-induced liver injury, we examined the effects of iron overload induced by ferric ammonium citrate (FAC) on oxidative stress and apoptosis signaling pathway in human hepatic cell line HH4. Methods and Results: Hepatic HH4 cells were exposed to FAC to force iron uptake, and cellular responses were determined. Incubation with 5 mM FAC resulted in increased intracellular iron content in a time-dependent manner. High concentration of FAC impaired cell viability and increased level of reactive oxygen species (ROS), and addition of antioxidant reagent such as glutathione or N-acetylcysteine dramatically reduced FAC-induced intracellular ROS generation. FAC overload significantly increased the phosphorylation of inhibitor of κB-α, p38 mitogen-activated protein kinase (MAPK), and nuclear factor κ light chain enhancer of activated B cells (NF-κB) p65 and promoted the nuclear translocation of NF-κB p65. Knockdown of Fas and Bid expression by small interfering RNA in iron-treated HH4 cells resulted in restoration of cell viability. Conclusions: We reported that FAC treatment is capable of inducing both extrinsic death receptor and intrinsic mitochondrial signaling pathway-mediated HH4 cells apoptosis through ROS-activated p38 MAPK and NF-κB pathways.