4-hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis-infected macrophages.
4-hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis-infected macrophages.
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DOI：
10.1053/j.gastro.2011.11.020
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发表时间：
2012-03
期刊：
影响因子：
29.4
通讯作者：
Huycke MM
中科院分区：
文献类型：
--
作者：
Wang X;Yang Y;Moore DR;Nimmo SL;Lightfoot SA;Huycke MM
粪肠球菌是一种人类肠道共生菌，可产生细胞外超氧化物，并通过巨噬细胞诱导的旁观者效应促进染色体不稳定。我们研究了 4-羟基-2-壬烯醛 (4-HNE)（一种 ω-6 多不饱和脂肪酸的扩散分解产物）介导这些效应的能力。 4-HNE从粪肠球菌感染的巨噬细胞中纯化；在人结肠癌 (HCT116) 和原代鼠结肠上皮 (YAMC) 细胞系中评估了其遗传毒性。 4-HNE 诱导 G2M 细胞周期停滞，导致形成 γH2AX 灶，并破坏两种细胞系中的有丝分裂纺锤体。与 4-HNE 孵育后形成的双核四倍体细胞与 Stathmin 的激活和微管灾难有关。沉默谷胱甘肽 S-转移酶 α-4（4-HNE 的清除剂）会增加上皮细胞对 4-HNE 诱导的遗传毒性的敏感性。被产生超氧化物的粪肠球菌定植的白细胞介素10敲除小鼠会出现炎症和结直肠癌，而被缺乏超氧化物的菌株定植会导致炎症，但不会导致癌症。在结直肠炎症区域的固有层和巨噬细胞中发现了 4-HNE-蛋白加合物。 4-HNE 可在正常结肠上皮细胞和结肠癌细胞中充当有丝分裂纺锤体毒物。这一发现将巨噬细胞诱导的旁观者效应与结直肠癌发生联系起来。
Enterococcus faecalis is a human intestinal commensal that produces extracellular superoxide and promotes chromosome instability via macrophage-induced bystander effects. We investigated the ability of 4-hydroxy-2-nonenal (4-HNE)—a diffusible breakdown product of ω-6 polyunsaturated fatty acids—to mediate these effects. 4-HNE was purified from E faecalis-infected macrophages; its genotoxicity was assessed in human colon cancer (HCT116) and primary murine colon epithelial (YAMC) cell lines. 4-HNE induced G2M cell cycle arrest, led to formation γH2AX foci, and disrupted the mitotic spindle in both cell lines. Binucleate tetraploid cells that formed following incubation with 4-HNE were associated with the activation of stathmin and microtubule catastrophe. Silencing glutathione S-transferase α-4, a scavenger of 4-HNE, increased susceptibility of epithelial cells to 4-HNE-induced genotoxicity. Interleukin-10 knockout mice colonized with superoxide-producing E faecalis developed inflammation and colorectal cancer, whereas colonization with a superoxide-deficient strain resulted in inflammation but not cancer. 4-HNE-protein adducts were found in the lamina propria and macrophages in areas of colorectal inflammation. 4-HNE can act as an autochthonous mitotic spindle poison in normal colonic epithelial and colon cancer cells. This finding links the macrophage-induced bystander effects to colorectal carcinogenesis.
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影响因子：
11.2
作者：
Lorimore, Sally A.;Chrystal, Jennifer A.;Wright, Eric G.
通讯作者：
Wright, Eric G.
影响因子：
4.7
作者：
Huycke, MM;Abrams, V;Moore, DR
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Moore, DR
影响因子：
6
作者：
Balish, E;Warner, T
通讯作者：
Warner, T
影响因子：
4.8
作者：
Manna, Tapas;Thrower, Douglas A.;Wilson, Leslie
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Wilson, Leslie
影响因子：
11.4
作者：
Czarneski, J;Lin, YC;Raveche, E
通讯作者：
Raveche, E