Anti-inflammatory effects of novel barbituric acid derivatives in T lymphocytes.
Anti-inflammatory effects of novel barbituric acid derivatives in T lymphocytes.
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新型巴比妥酸衍生物对 T 淋巴细胞的抗炎作用。
DOI：
10.1016/j.intimp.2016.06.004
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发表时间：
2016
影响因子：
5.6
通讯作者：
Chiles,ThomasC
中科院分区：
文献类型：
--
作者：
Xu,Chenjia;Wyman,ArleneR;Alaamery,ManalA;Argueta,ShannonA;Ivey,FDouglas;Meyers,JohnA;Lerner,Adam;Burdo,TriciaH;Connolly,Timothy;Hoffman,CharlesS;Chiles,ThomasC
我们已经使用了高通量的小分子筛选，使用裂变酵母为基础的测定，以确定新的磷酸二酯酶7（PDE 7）抑制剂。最有效的命中化合物之一是BC 12，这是一种基于巴比妥酸的分子，对T淋巴细胞功能表现出异常强效的免疫抑制和免疫调节作用，包括抑制T细胞增殖和IL-2细胞因子产生。BC 12处理在植物血凝素（PHA）加佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）刺激的Jurkat T细胞中赋予> 95%的IL-2分泌抑制。BC 12对IL-2分泌的影响不是由于细胞活力降低;相反，BC 12阻断活化T细胞中IL-2转录的上调。BC 12还抑制响应于CD 3/CD 28共连接或PMA和离子霉素的组合而刺激的人外周T淋巴细胞中的IL-2分泌，以及用PMA和离子霉素刺激的原代鼠T细胞的增殖。缺乏PDE 7抑制活性的BC 12类似物（BC 12 -4）显示出相似的生物活性，表明BC 12不通过PDE 7抑制起作用。为了研究BC 12抑制IL-2产生的机制，我们在存在或不存在BC 12或BC 12 -4的情况下使用未刺激的和刺激的Jurkat T细胞进行微阵列分析。我们的研究表明，这些化合物会影响对刺激的转录反应，并通过一个或多个共同的靶点发挥作用，从而产生抗炎和促应激作用。这些结果证明了BC 12和BC 12 -4在T淋巴细胞中的有效免疫调节活性，并提示了作为免疫调节剂治疗T淋巴细胞介导的疾病的潜在临床用途。
We have used a high throughput small molecule screen, using a fission yeast-based assay, to identify novel phosphodiesterase 7 (PDE7) inhibitors. One of the most effective hit compounds was BC12, a barbituric acid-based molecule that exhibits unusually potent immunosuppressive and immunomodulatory actions on T lymphocyte function, including inhibition of T cell proliferation and IL-2 cytokine production. BC12 treatment confers a > 95% inhibition of IL-2 secretion in phytohaemagglutinin (PHA) plus phorbol-12-myristate-13-acetate (PMA) stimulated Jurkat T cells. The effect of BC12 on IL-2 secretion is not due to decreased cell viability; rather, BC12 blocks up-regulation of IL-2 transcription in activated T cells. BC12 also inhibits IL-2 secretion in human peripheral T lymphocytes stimulated in response to CD3/CD28 co-ligation or the combination of PMA and ionomycin, as well as the proliferation of primary murine T cells stimulated with PMA and ionomycin. A BC12 analog that lacks PDE7 inhibitory activity (BC12-4) displays similar biological activity, suggesting that BC12 does not act via PDE7 inhibition. To investigate the mechanism of inhibition of IL-2 production by BC12, we performed microarray analyses using unstimulated and stimulated Jurkat T cells in the presence or absence of BC12 or BC12-4. Our studies show these compounds affect the transcriptional response to stimulation and act via one or more shared targets to produce both anti-inflammatory and pro-stress effects. These results demonstrate potent immunomodulatory activity for BC12 and BC12-4 in T lymphocytes and suggest a potential clinical use as an immunotherapeutic to treat T lymphocyte-mediated diseases.