Signaling mechanisms in tumor necrosis factor alpha-induced death of microvascular endothelial cells of the corpus luteum.
Signaling mechanisms in tumor necrosis factor alpha-induced death of microvascular endothelial cells of the corpus luteum.
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DOI：
10.1186/1477-7827-1-17
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发表时间：
2003-02-11
期刊：
影响因子：
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通讯作者：
Rueda, Bo R
中科院分区：
文献类型：
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作者：
Pru, James K;Lynch, Maureen P;Rueda, Bo R
黄体微血管构筑占黄体细胞总数的50%以上，被认为是黄体溶解过程中第一个通过细胞凋亡而变性的结构。这些研究比较了不同细胞因子(肿瘤坏死因子α、干扰素γ、可溶性Fas配体、Fas激活抗体和黄体溶解激素前列腺素F2pha)对CL来源的内皮细胞(CLENDO)的凋亡潜能。SFasL、FasAb和PGF2α对CLENDO细胞存活率均无影响。利用形态和生化参数，很明显，在长期培养中，TNFpha和IFNGamma启动了细胞凋亡。然而，在早期时间点，肿瘤坏死因子α是最有效的刺激CLENDO细胞凋亡的因素。与许多在非生殖细胞类型中描述的其他研究不同，TNFpha诱导CLENDO细胞凋亡是在没有蛋白质合成抑制剂的情况下发生的。肿瘤坏死因子α诱导的死亡通常与不同的细胞内信号通路(如MAPK和鞘磷脂通路)的急性激活有关。用肿瘤坏死因子α处理5-30分钟激活了MAPK(ERK、p38和JNK)，并增加了神经酰胺的积累。神经酰胺是鞘磷脂水解的产物，在多种细胞类型中可以独立地作为MAPK家族成员的上游激活剂，是一种成熟的促凋亡第二信使。与肿瘤坏死因子α一样，外源性神经酰胺处理CLENDO细胞可显著诱导内皮细胞凋亡。神经酰胺也激活JNK通路，但对ERK和p38MAPKs无影响。谷胱甘肽(GSH)是一种细胞内还原剂，也是已知的活性氧簇(ROS)或肿瘤坏死因子α(TNFpha)诱导的凋亡的抑制剂，用GSH预处理CLENDO细胞后，显著减弱了TNFpha诱导的细胞凋亡。据推测，TNFpha通过增加活性氧物种和促进细胞凋亡的细胞内信号来杀死CLENDO细胞。
The microvasculature of the corpus luteum (CL), which comprises greater than 50% of the total number of cells in the CL, is thought to be the first structure to undergo degeneration via apoptosis during luteolysis. These studies compared the apoptotic potential of various cytokines (tumor necrosis factor alpha, TNFalpha; interferon gamma, IFNgamma; soluble Fas ligand, sFasL), a FAS activating antibody (FasAb), and the luteolytic hormone prostaglandin F2alpha (PGF2alpha) on CL-derived endothelial (CLENDO) cells. Neither sFasL, FasAb nor PGF2alpha had any effect on CLENDO cell viability. Utilizing morphological and biochemical parameters it was evident that TNFalpha and IFNgamma initiated apoptosis in long-term cultures. However, TNFalpha was the most potent stimulus for CLENDO cell apoptosis at early time points. Unlike many other studies described in non-reproductive cell types, TNFalpha induced apoptosis of CLENDO cells occurs in the absence of inhibitors of protein synthesis. TNFalpha-induced death is typically associated with acute activation of distinct intracellular signaling pathways (e.g. MAPK and sphingomyelin pathways). Treatment with TNFalpha for 5-30 min activated MAPKs (ERK, p38, and JNK), and increased ceramide accumulation. Ceramide, a product of sphingomyelin hydrolysis, can serve as an upstream activator of members of the MAPK family independently in numerous cell types, and is a well-established pro-apoptotic second messenger. Like TNFalpha, treatment of CLENDO cells with exogenous ceramide significantly induced endothelial apoptosis. Ceramide also activated the JNK pathway, but had no effect on ERK and p38 MAPKs. Pretreatment of CLENDO cells with glutathione (GSH), an intracellular reducing agent and known inhibitor of reactive oxygen species (ROS) or TNFalpha-induced apoptosis, significantly attenuated TNFalpha-induced apoptosis. It is hypothesized that TNFalpha kills CLENDO cells through elevation of reactive oxygen species, and intracellular signals that promote apoptosis.