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首页> 外文期刊>Archives of Toxicology >Detection of the mechanism of immunotoxicity of cyclosporine A in murine in vitro and in vivo models
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Detection of the mechanism of immunotoxicity of cyclosporine A in murine in vitro and in vivo models

机译：在体外和体内鼠中鼠孢子A中的免疫毒性机理检测

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Transcriptomics in combination with in vitro cell systems is a powerful approach to unravel modes of action of toxicants. An important question is to which extent the modes of action as revealed by transcriptomics depend on cell type, species and study type (in vitro or in vivo). To acquire more insight into this, we assessed the transcriptomic effects of the immunosuppressive drug cyclosporine A (CsA) upon 6 h of exposure of the mouse cytotoxic T cell line CTLL-2, the thymoma EL-4 and primary splenocytes and compared these to the effects in spleens of mice orally treated with CsA for 7 days. EL-4 and CTLL-2 cells showed the highest similarities in response. CsA affected many genes in primary splenocytes that were not affected in EL-4 or CTLL-2. Pathway analysis demonstrated that CsA upregulated the unfolded protein response, endoplasmic reticulum stress and NRF2 activation in EL-4 cells, CTLL-2 cells and primary mouse splenocytes but not in mouse spleen in vivo. As expected, CsA downregulated cell cycle and immune response in splenocytes in vitro, spleens in vivo as well as CTLL-2 in vitro. Genes up- and downregulated in human Jurkat, HepG2 and renal proximal tubular cells were similarly affected in CTLL-2, EL-4 and primary splenocytes in vitro. In conclusion, of the models tested in this study, the known mechanism of immunotoxicity of CsA is best represented in the mouse cytotoxic T cell line CTLL-2. This is likely due to the fact that this cell line is cultured in the presence of a T cell activation stimulant (IL-2) making it more suitable to detect inhibitory effects on T cell activation.
机译：转录组合与体外细胞体系组合是一种强大的毒物作用方式的强大方法。重要的问题是转录组织揭示的行动模式在哪种程度上取决于细胞类型，物种和研究类型（体外或体内）。要获得更多的洞察力，我们评估了免疫抑制药物环孢菌素A（CSA）的转录组效应在小鼠细胞毒性T细胞系CTLL-2，胸腺瘤EL-4和原发性脾细胞的暴露后6小时，并将其与其进行比较用CSA口服对小鼠脾脏的影响7天。 EL-4和CTLL-2细胞显示出最高的相似性。 CSA在EL-4或CTLL-2中不受影响的原发性脾细胞中影响了许多基因。途径分析表明，CSA上调了EL-4细胞，CTLL-2细胞和初级小鼠脾细胞的展开蛋白质反应，内质网应激和NRF2活化，但不在体内小鼠脾脏中。正如预期的那样，CSA在体外，体内脾脏的脾细胞中的细胞周期和免疫应答以及体外CTLL-2中的脾细胞。在人的Jurkat，HepG2和肾近端管状细胞中升级和下调的基因在CTLL-2，EL-4和原发脾细胞中类似地影响。总之，在本研究中测试的模型中，CSA的免疫毒性的已知机制最佳地代表在小鼠细胞毒性T细胞系CTLL-2中。这可能是由于该细胞系在T细胞活化刺激物（IL-2）存在下培养，使其更适合于检测对T细胞活化的抑制作用。

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