Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines
Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines
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DOI：
10.1016/j.freeradbiomed.2020.09.023
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发表时间：
2020-12-01
影响因子：
7.4
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Ishida, Noriko;Aoki, Yuichi;Yamamoto, Masayuki
人淋巴母细胞系（LCL）对于疾病的功能分析很有价值。我们已经建立了超过 4200 个拼箱作为综合生物样本库的资源之一。虽然氧化和炎症应激在各种疾病的发生和进展中发挥着关键作用，但 LCL，尤其是生物库制造的 LCL，对这些应激的反应尚未确定。为了解决 LCL 如何响应这些压力，在本研究中，我们对 11 种用亲电子试剂马来酸二乙酯 (DEM) 和/或炎症介质脂多糖 (LPS) 处理的人类 LCL 进行了 RNA 测序。我们发现，在用 DEM 处理的 LCL 中，超过 2000 个基因（包括由亲电/氧化应激反应的主调节因子 NRF2 调节的基因）上调，而在用 LPS 处理的 LCL 中，大约 300 个基因（包括炎症相关基因）上调。在 LPS 诱导的基因中，一部分促炎基因被 DEM 抑制，这支持了 DEM 通过 NRF2 激活抑制促炎基因表达的观点。相反，DEM 诱导的基因的一部分被 LPS 抑制，表明亲电子和炎症应激介导的途径之间存在相互干扰。这些数据清楚地表明，LCL 总体上维持着针对氧化和炎症应激的响应途径，并进一步证实了生物库中 LCL 供应的有用性。
Human lymphoblastoid cell lines (LCLs) are valuable for the functional analyses of diseases. We have established more than 4200 LCLs as one of the resources of an integrated biobank. While oxidative and inflammatory stresses play critical roles in the onset and progression of various diseases, the responsiveness of LCLs, especially that of biobank-made LCLs, to these stresses has not been established. To address how LCLs respond to these stresses, in this study, we performed RNA sequencing of eleven human LCLs that were treated with an electrophile, diethyl maleate (DEM) and/or an inflammatory mediator, lipopolysaccharide (LPS). We found that over two thousand genes, including those regulated by a master regulator of the electrophilic/oxidative stress response, NRF2, were upregulated in LCLs treated with DEM, while approximately three hundred genes, including inflammation-related genes, were upregulated in LPS-treated LCLs. Of the LPS-induced genes, a subset of proinflammatory genes was repressed by DEM, supporting the notion that DEM suppresses the expression of proinflammatory genes through NRF2 activation. Conversely, a part of DEM-induced gene was repressed by LPS, suggesting reciprocal interference between electrophilic and inflammatory stress-mediated pathways. These data clearly demonstrate that LCLs maintain, by and large, responsive pathways against oxidative and inflammatory stresses and further endorse the usefulness of the LCL supply from the biobank.