A manganese superoxide dismutase (SOD2)-mediated adaptive response.
A manganese superoxide dismutase (SOD2)-mediated adaptive response.
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DOI：
10.1667/rr3126.2
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发表时间：
2013-02
影响因子：
3.4
通讯作者：
Weichselbaum RR
中科院分区：
文献类型：
--
作者：
Grdina DJ;Murley JS;Miller RC;Mauceri HJ;Sutton HG;Thirman MJ;Li JJ;Woloschak GE;Weichselbaum RR
极低剂量的电离辐射（5至100毫戈瑞）可诱发适应性反应，其特点是提高细胞存活率和减少微核形成。利用这些终点，RKO人结肠癌和转化的小鼠胚胎成纤维细胞（MEF）、缺失TNF受体1和2的野生型或敲除细胞（TNFR 1 −R2−）和C57 BL/6和TNFR 1 −R2−敲除小鼠，我们证明了完整的TNF信号是诱导锰超氧化物歧化酶（SOD 2）活性升高所必需的。（P < 0.001）以及当细胞在稍后时间用2戈伊攻击时这些SOD 2介导的适应性应答的随后表达。相比之下，氨磷汀的游离巯基形式WR 1065可以直接激活NF-κB，24 h后引起SOD 2活性升高，并在MEF野生型和TNF信号缺陷型TNFR 1 −R2−细胞中诱导适应性反应。用SOD 2 siRNA转染细胞完全消除了SOD 2活性的升高和适应性反应的表达。这些结果在体内得到了证实，采用了C57 BL/6和TNFR 1 −R2−敲除小鼠脾细胞的微核试验，这些小鼠在暴露于2戈伊全身剂量前24小时暴露于100 mGy或400 mg/kg氨磷汀。100 mGy的剂量也增强了对暴露于100 mg/kg N-乙基-N-亚硝基脲（ENU）24 h后的C57 BL/6小鼠的保护作用。虽然非常低的辐射剂量需要完整的TNF信号传导过程来诱导SOD 2介导的适应性反应，但氨磷汀可以分别在TNF受体感受态细胞和敲除细胞中诱导类似的适应性反应。
Very low doses of ionizing radiation, 5 to 100 mGy, can induce adaptive responses characterized by elevation in cell survival and reduction in micronuclei formation. Utilizing these end points, RKO human colon carcinoma and transformed mouse embryo fibroblasts (MEF), wild-type or knockout cells missing TNF receptors 1 and 2 (TNFR1−R2−), and C57BL/6 and TNFR1−R2− knockout mice, we demonstrate that intact TNF signaling is required for induction of elevated manganese superoxide dismutase (SOD2) activity (P < 0.001) and the subsequent expression of these SOD2-mediated adaptive responses when cells are challenged at a later time with 2 Gy. In contrast, amifostine’s free thiol form WR1065 can directly activate NF-κB giving rise to elevated SOD2 activity 24 h later and induce an adaptive response in both MEF wild-type and TNF signaling defective TNFR1−R2− cells. Transfection of cells with SOD2 siRNA completely abolishes both the elevation in SOD2 activity and expression of the adaptive responses. These results were confirmed in vivo using a micronucleus assay in splenocytes derived from C57BL/6 and TNFR1−R2− knockout mice that were exposed to 100 mGy or 400 mg/kg amifostine 24 h prior to exposure to a 2 Gy whole-body dose. A dose of 100 mGy also conferred enhanced protection to C57BL/6 mice exposed 24 h later to 100 mg/kg of N-Ethyl-N-nitrosourea (ENU). While very low radiation doses require an intact TNF signaling process to induce a SOD2-mediated adaptive response, amifostine can induce a similar adaptive response in both TNF receptor competent and knockout cells, respectively.