Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation
Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation
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DOI：
10.1158/0008-5472.can-08-0698
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Wright, Eric G.
中科院分区：
文献类型：
--
作者：
Lorimore, Sally A.;Chrystal, Jennifer A.;Wright, Eric G.
电离辐射的致瘤潜力通常被归因于照射时诱导的受照射细胞中的DNA损伤。最近，有越来越多的报告，在未照射的细胞，无论是邻居或后代的照射细胞，分别被视为旁观者效应和基因组不稳定性，统称为非靶向效应的损害。在这项研究中，我们表明，正常小鼠造血克隆干细胞的后代暴露于骨髓条件培养基来自γ射线照射的小鼠表现出染色体不稳定性，不像直接γ射线照射的细胞的后代。这种不稳定性在辐射诱导的急性髓性白血病（r-AML）敏感株（CBA/Ca）的骨髓细胞中表达，但在对r-AML耐药的小鼠（C57 BL/6）中不表达。此外，交叉遗传实验表明，不稳定表型的诱导需要生产者和应答者细胞都是易感CBA/Ca基因型。巨噬细胞是旁观者信号的来源，信号机制涉及肿瘤坏死因子-α、一氧化氮和超氧化物。研究结果表明，辐射诱导的巨噬细胞介导的旁观者信号诱导的基因型依赖性染色体不稳定表型。由于大多数电离辐射的意外、职业和治疗暴露都是部分身体暴露，因此这些发现对理解此类暴露的后果具有影响。
The tumorigenic potential of ionizing radiation has conventionally been attributed to DNA damage in irradiated cells induced at the time of exposure. Recently, there have been an increasing number of reports of damage in unirradiated cells that are either neighbors or descendants of irradiated cells, respectively, regarded as bystander effects and genomic instability and collectively termed nontargeted effects. In this study, we show that descendants of normal murine hemaopoietic clonogenic stem cells exposed to bone marrow-conditioned medium derived from gamma-irradiated mice exhibit chromosomal instability unlike the descendants of directly gamma-irradiated cells. The instability is expressed in bone marrow cells of the radiation-induced acute myeloid leukemia (r-AML) susceptible strain (CBA/Ca) but not in mice resistant to r-AML (C57BL/6). Furthermore, crossgenetic experiments show the induction of the instability phenotype requires both the producer and responder cells to be of the susceptible CBA/Ca genotype. Macrophages are the source of the bystander signals, and the signaling mechanism involves tumor necrosis factor-alpha, nitric oxide, and superoxide. The findings show a genotype-dependent chromosomal instability phenotype induced by radiation-induced macrophage-mediated bystander signaling. As the majority of accidental, occupational, and therapeutic exposures to ionizing radiation are partial body exposures, the findings have implications for understanding the consequences of such exposure.