Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells
Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells
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DOI：
10.1073/pnas.1913707117
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发表时间：
2020-05-05
影响因子：
11.1
通讯作者：
Munoz-Pinedo, Cristina
中科院分区：
文献类型：
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作者：
Puschel, Franziska;Favaro, Francesca;Munoz-Pinedo, Cristina
细胞饥饿通常是组织损伤的结果，这种损伤扰乱了当地的血液供应，但也可能发生在细胞数量超过当地血管系统的地方，如实体肿瘤中所观察到的。细胞对营养缺乏的反应是通过调整新陈代谢，或者，如果饥饿时间延长，可能会导致细胞死亡。细胞饥饿还会触发适应性反应，如血管生成，从而促进组织重组和修复，但其他适应性反应及其介体的特征仍然很差。为了探索这个问题，我们分析了葡萄糖剥夺细胞的分泌体，揭示了多种细胞因子和趋化因子，包括IL-6和IL-8，在饥饿应激下上调。饥饿诱导的细胞因子依赖于细胞类型，它们也是从原代上皮细胞释放出来的。大多数细胞因子的上调依赖于与IL-8启动子直接结合的整合应激反应ATF4的转录因子和核因子-kappaB。此外，剥夺谷氨酰胺，以及抗代谢药物2-脱氧葡萄糖和二甲双胍也促进了IL-6和IL-8的释放。最后，饥饿细胞释放的一些因子可以诱导B细胞、巨噬细胞和中性粒细胞的趋化，这表明肿瘤环境中的营养剥夺可能是肿瘤炎症的始动因素。
Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-kappa B and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.