Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, CH-8057 Zurich, Switzerland.
Institute of Anatomy, Faculty of Medicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Int J Mol Sci. 2019 Jan 20;20(2):436. doi: 10.3390/ijms20020436.
Immune system deterioration in space represents a major risk, which has to be mitigated for exploration-class missions into the solar system. Altered gravitational forces have been shown to regulate adaptation processes in cells of the immune system, which are important for appropriate risk management, monitoring and development of countermeasures. T lymphocytes and cells of the monocyte-macrophage system are highly migratory cell types that frequently encounter a wide range of oxygen tensions in human tissues and in hypoxic areas, even under homeostatic conditions. Hypoxia-inducible factor 1 and 2 (HIF's) might have an important role in activation of T cells and cells of the monocyte-macrophages system. Thus, we investigated the regulation of HIF-dependent and, therefore, hypoxia-signaling systems in both cell types in altered gravity and performed transcript and protein analysis from parabolic flight and suborbital ballistic rocket experiments. We found that HIF-1α and HIF-1-dependent transcripts were differently regulated in altered gravity, whereas HIF-1α-dependent gene expression adapted after 5 min microgravity. Inter-platform comparisons identified PDK1 as highly responsive to gravitational changes in human U937 myelomonocytic cells and in Jurkat T cells. We suggest HIF-1 as a potential pharmacological target for counteracting immune system deterioration during space flight.
太空环境中的免疫系统恶化是一个主要风险，这对于太阳系探索任务来说必须加以缓解。已证明，改变的引力会调节免疫系统细胞的适应过程，这对于适当的风险管理、监测和对策开发非常重要。T 淋巴细胞和单核细胞-巨噬细胞系统的细胞是高度迁移的细胞类型，即使在稳态条件下，它们也经常在人体组织和缺氧区域中遇到广泛的氧气张力。缺氧诱导因子 1 和 2（HIFs）可能在 T 细胞和单核细胞-巨噬细胞系统的激活中发挥重要作用。因此，我们研究了在改变的重力下这两种细胞类型中 HIF 依赖性和因此缺氧信号系统的调节，并进行了抛物线飞行和亚轨道弹道火箭实验的转录和蛋白质分析。我们发现，在改变的重力下，HIF-1α 和 HIF-1 依赖性转录物的调节不同，而 HIF-1α 依赖性基因表达在微重力 5 分钟后适应。平台间比较确定 PDK1 对人 U937 髓样单核细胞和 Jurkat T 细胞中的重力变化高度敏感。我们建议 HIF-1 作为对抗太空飞行中免疫系统恶化的潜在药物靶点。
