Meisoindigo attenuates dextran sulfate sodium-induced experimental colitis via its inhibition of TAK1 in macrophages
Meisoindigo attenuates dextran sulfate sodium-induced experimental colitis via its inhibition of TAK1 in macrophages
复制标题
甲异靛通过抑制巨噬细胞中的 TAK1 来减轻葡聚糖硫酸钠诱导的实验性结肠炎。
DOI：
10.1016/j.intimp.2021.108239
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Xu Q
中科院分区：
文献类型：
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作者：
Wang J Shi K Li S Chen L Liu W Wu X Shen Y;Sun Y Cheng J;Wu XF;Xu Q
目前，炎症性肠病（IBD）严重威胁着人类的健康，其治疗是人们面临的巨大挑战。在我们的研究中，我们发现靛玉红的衍生物甲异靛，显着改善葡聚糖硫酸钠（DSS）诱导的小鼠实验性结肠炎。甲异靛处理显著提高谷胱甘肽水平，而抑制碱性磷酸酶和髓过氧化物酶的活性在结肠组织。此外，甲异靛治疗后，结肠炎相关分子血管细胞粘附分子1、细胞间粘附分子1、环氧合酶2的mRNA表达以及炎症细胞因子白细胞介素（IL）-18、IL-1β、IL-6、肿瘤坏死因子（TNF）-α和诱导型一氧化氮合酶（iNOS）的水平均呈剂量依赖性抑制。免疫荧光结果显示甲异靛抑制DSS处理小鼠结肠巨噬细胞浸润和核因子（NF）-κB活化。因此，在体外，用脂多糖（LPS）单独或联合三磷酸腺苷（ATP）处理小鼠RAW 264. 7和人THP-1细胞以激活NF-κB通路。结果表明，甲异靛可降低LPS处理后两种细胞中NO、IL-18、IL-1β和TNF-α水平的升高。此外，甲异靛通过使用依赖于NF-κB的荧光素酶报告基因显示出对NF-κ B的抑制作用。通过分子对接、微量热泳和细胞热位移分析。进一步发现甲异靛靶向作用于NF-κB通路上游的重要调节因子转化生长因子β激活激酶1（TAK 1）。结论：甲异靛在低剂量下可有效缓解IBD，并通过抑制TAK 1的活化负性调节促炎反应，为临床抗炎治疗提供了新的思路。
At present, inflammatory bowel disease (IBD) seriously threatens human health, and its treatment is a huge challenge for people. In our studies, we found that meisoindigo, a derivative of indirubin, significantly ameliorated dextran sulfate sodium (DSS)-induced experimental colitis in mice. Meisoindigo treatment markedly elevated the level of glutathione, while suppressed the activities of alkaline phosphatase and myeloperoxidase in colonic tissues. Moreover, the mRNA expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, cyclooxygenase-2 which are important colitis-related molecules and the levels of the inflammatory cytokines interleukin (IL)-18, IL-1β, IL-6, tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) were suppressed dose-dependently following treatment with meisoindigo. Immunofluorescence results indicated that meisoindigo inhibited macrophage infiltration and nuclear factor (NF)-κB activation in colons from DSS-treated mice. Therefore, mouse RAW264.7 and human THP-1 cells were treated with lipopolysaccharide (LPS) alone or combined adenosine triphosphate to activate NF-κB pathwayin vitro. It was shown that meisoindigo reduced the elevated levels of NO, IL-18, IL-1β and TNF-α after LPS treatment in both cells. In addition, meisoindigo showed inhibitory effects on NF-κB by using a luciferase reporter gene that depends on NF-κB. Through molecular docking, microscale thermophoresis and cellular thermal shift assay. It was further found that meisoindigo targeted transforming growth factor β activated kinase-1 (TAK1), which is an important regulator in the upstream of NF-κB pathway. In conclusion, our findings show that meisoindigo can alleviate IBD effectively at low doses, and negatively regulate proinflammatory responses by inhibiting the activation of TAK1, which provides new ideas for clinical anti-inflammatory therapy.