Hübner Max, Effinger David, Wu Tingting, Strauß Gabriele, Pogoda Kristin, Kreth Friedrich-Wilhelm, Kreth Simone
Department of Anesthesiology, University Hospital, LMU Munich, 81377 Munich, Germany.
Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, 81377 Munich, Germany.
Cancers (Basel). 2020 Feb 13;12(2):433. doi: 10.3390/cancers12020433.
The recombinant IL-1 receptor antagonist anakinra-currently approved for the treatment of autoinflammatory diseases-blocks IL-1β-mediated inflammatory signaling. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness.
Primary GBM or T98G cells were incubated alone or with peripheral blood mononuclear cells (PBMCs) and were subsequently treated with IL-1β and/or anakinra. T cells were obtained by magnetic bead isolation. Protein and mRNA expression were quantified by SDS-PAGE, qRT-PCR, and ELISA, respectively. Cell proliferation and apoptosis were analyzed via flow cytometry. Chemotaxis was studied via time-lapse microscopy.
Upon IL-1β stimulation, anakinra attenuated proinflammatory gene expression in both GBM cells and PBMCs, and mitigated tumor migration and proliferation. In a more lifelike model replacing IL-1β stimulation by GBM-PBMC co-culture, sole presence of PBMCs proved sufficient to induce a proinflammatory phenotype in GBM cells with enhanced proliferation and migration rates and attenuated apoptosis. Anakinra antagonized these pro-tumorigenic effects and, moreover, reduced inflammatory signaling in T cells without compromising anti-tumor effector molecules.
By dampening the inflammatory crosstalk between GBM and immune cells, anakinra mitigated GBM aggressiveness. Hence, counteracting IL-1β-mediated inflammation might be a promising strategy to pursue.
重组白细胞介素-1受体拮抗剂阿那白滞素——目前已被批准用于治疗自身炎症性疾病——可阻断白细胞介素-1β介导的炎症信号传导。由于炎症是癌症的主要驱动因素，我们推测阿那白滞素可能能够减轻胶质母细胞瘤（GBM）的侵袭性。
将原发性GBM或T98G细胞单独培养或与外周血单个核细胞（PBMC）共同培养，随后用白细胞介素-1β和/或阿那白滞素进行处理。通过磁珠分离获得T细胞。分别通过SDS-PAGE、qRT-PCR和ELISA对蛋白质和mRNA表达进行定量分析。通过流式细胞术分析细胞增殖和凋亡情况。通过延时显微镜研究趋化性。
在白细胞介素-1β刺激下，阿那白滞素可减弱GBM细胞和PBMC中的促炎基因表达，并减轻肿瘤迁移和增殖。在一个更接近真实情况的模型中，用GBM-PBMC共培养替代白细胞介素-1β刺激，结果表明仅PBMC的存在就足以在GBM细胞中诱导促炎表型，使其增殖和迁移速率提高，凋亡减弱。阿那白滞素可拮抗这些促肿瘤作用，此外，还可降低T细胞中的炎症信号传导，而不影响抗肿瘤效应分子。
通过抑制GBM与免疫细胞之间的炎症串扰，阿那白滞素减轻了GBM的侵袭性。因此，对抗白细胞介素-1β介导的炎症可能是一种有前景的策略。
