Biased signalling is an essential feature of TLR4 in glioma cells.
Biased signalling is an essential feature of TLR4 in glioma cells.
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DOI：
10.1016/j.bbamcr.2016.09.016
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发表时间：
2016-12
期刊：
影响因子：
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通讯作者：
Marie-Theres Zeuner;Carmen L Krüger;K. Volk;K. Bieback;G. Cottrell;M. Heilemann;D. Widera
中科院分区：
文献类型：
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作者：
Marie-Theres Zeuner;Carmen L Krüger;K. Volk;K. Bieback;G. Cottrell;M. Heilemann;D. Widera
Toll样受体4(TLR4)的一个明显特征是它能够同时触发MyD88依赖和MyD88非依赖的信号转导，最终激活促炎的NF-κB和/或抗病毒IRF3。尽管来自不同细菌的TLR4激动剂(脂多糖)具有不同的内毒素活性，但内毒素化学型对下游信号转导的影响尚不完全清楚。值得注意的是，不同的TLR4激动剂在胶质瘤动物模型中表现出抗肿瘤活性，但其潜在的分子机制很大程度上尚不清楚。因此，我们研究了内毒素化学型对人胶质瘤细胞系U251信号转导事件的影响。我们发现，与明尼苏达州沙门氏菌来源的脂多糖(LPSSM)相比，大肠杆菌内毒素(LPSEC)导致了NF-κB偏向的下游信号转导。与LPSSM相比，U251细胞暴露于LPSEC后，其核转位速度加快，NF-κB活性和靶基因表达增加，IL-6分泌量增加。利用超分辨显微镜，我们发现TLR4在胶质瘤细胞中的偏向激动性既不是受体密度的不同调节的结果，也不是更高阶低聚物形成的结果。与以前的报道一致，LPSEC介导的NF-κB激活导致U251细胞的增殖显著增加，而LPSSM诱导的IRF3活性对其侵袭性产生负面影响。最后，甲基-β-环糊精可选择性地增加LPSSM诱导的p65核转位和核因子-κB活性，而不影响IRF3。我们的数据可能解释了TLR4激动剂如何以不同的方式影响胶质瘤细胞的增殖和迁移。
A distinct feature of the Toll-like receptor 4 (TLR4) is its ability to trigger both MyD88-dependent and MyD88-independent signalling, culminating in activation of pro-inflammatory NF-κB and/or the antiviral IRF3. Although TLR4 agonists (lipopolysaccharides; LPSs) derived from different bacterial species have different endotoxic activity, the impact of LPS chemotype on the downstream signalling is not fully understood. Notably, different TLR4 agonists exhibit anti-tumoural activity in animal models of glioma, but the underlying molecular mechanisms are largely unknown.Thus, we investigated the impact of LPS chemotype on the signalling events in the human glioma cell line U251. We found that LPS ofEscherichia coliorigin (LPSEC) leads to NF-κB-biased downstream signalling compared toSalmonella minnesota-derived LPS (LPSSM). Exposure of U251 cells to LPSECresulted in faster nuclear translocation of the NF-κB subunit p65, higher NF-κB-activity and expression of its targets genes, and higher amount of secreted IL-6 compared to LPSSM. Using super-resolution microscopy we showed that the biased agonism of TLR4 in glioma cells is neither a result of differential regulation of receptor density nor of formation of higher order oligomers. Consistent with previous reports, LPSEC-mediated NF-κB activation led to significantly increased U251 proliferation, whereas LPSSM-induced IRF3 activity negatively influenced their invasiveness. Finally, treatment with methyl-β-cyclodextrin (MCD) selectively increased LPSSM-induced nuclear translocation of p65 and NF-κB activity without affecting IRF3.Our data may explain how TLR4 agonists differently affect glioma cell proliferation and migration.