胶质瘤干细胞而非大块胶质瘤细胞通过toll样受体4信号上调小胶质细胞/脑巨噬细胞IL-6分泌

Omar Dildar a Dzaye, F. Hu, K. Derkow, Verena Haage, P. Euskirchen, C. Harms, S. Lehnardt, M. Synowitz, S. Wolf, H. Kettenmann
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引用次数: 60

摘要

外周巨噬细胞和常驻小胶质细胞构成胶质瘤浸润细胞的优势。肿瘤在这些胶质瘤相关的小胶质细胞/脑巨噬细胞(GAMs)中诱导免疫抑制和肿瘤支持表型。胶质瘤细胞的一个亚群充当胶质瘤干细胞(GSCs)。我们探索了GSCs和GAMs之间的相互作用。以CD133为干性标记,采用荧光活化细胞分选(FACS)富集或剥夺小鼠胶质瘤细胞系GL261的GSCs。在相同的时间内,100个CD133+ GSCs具有形成肿瘤的能力,其大小与10,000个CD133- GL261细胞形成的肿瘤相当。在IL-6-/-小鼠中,只有CD133+细胞形成的肿瘤比野生型更小。用富含cd133的GL261胶质瘤细胞培养液刺激原代培养的小胶质细胞后,我们观察到依赖toll样受体(TLR) 4的小胶质细胞IL-6分泌选择性上调。我们的研究结果表明,GSCs而不是大块胶质瘤细胞通过TLR4信号启动小胶质细胞IL-6的分泌,IL-6通过支持GSCs来调节胶质瘤的生长。使用人类胶质瘤组织,我们可以证实GAMs是肿瘤环境中IL-6的主要来源。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling
Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133+ GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133- GL261 cells. In IL-6-/- mice, only tumors formed by CD133+ cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.
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