Abstract
In our study we aimed to identify rapidly reacting gravity-responsive mechanisms in mammalian cells in order to understand if and how altered gravity is translated into a cellular response. In a combination of experiments using "functional weightlessness" provided by 2D-clinostats and real microgravity provided by several parabolic flight campaigns and compared to in-flight-1g-controls, we identified rapid gravity-responsive reactions inside the cell cycle regulatory machinery of human T lymphocytes. In response to 2D clinorotation, we detected an enhanced expression of p21 Waf1/Cip1 protein within minutes, less cdc25C protein expression and enhanced Ser147-phosphorylation of cyclinB1 after CD3/CD28 stimulation. Additionally, during 2D clinorotation, Tyr-15-phosphorylation occurred later and was shorter than in the 1 g controls. In CD3/CD28-stimulated primary human T cells, mRNA expression of the cell cycle arrest protein p21 increased 4.1-fold after 20s real microgravity in primary CD4+ T cells and 2.9-fold in Jurkat T cells, compared to 1 g in-flight controls after CD3/CD28 stimulation. The histone acetyltransferase (HAT) inhibitor curcumin was able to abrogate microgravity-induced p21 mRNA expression, whereas expression was enhanced by a histone deacetylase (HDAC) inhibitor. Therefore, we suppose that cell cycle progression in human T lymphocytes requires Earth gravity and that the disturbed expression of cell cycle regulatory proteins could contribute to the breakdown of the human immune system in space.
Highlights
Gravity has been a constant force throughout evolutionary history on Earth
We recently developed an experimental system which for the first time allows for large-scale cell culture experiments with living mammalian cells on board of the parabolic flight aircraft Airbus A300 ZERO-G [31]
Experiments in simulated weightlessness (2D clinorotation) Because long-term in vitro studies clearly revealed that T cells lost their proliferative capacity in microgravity [8,9], we first investigated key molecules of cell cycle control in short-term simulated weightlessness provided by 2D clinorotation of PMA-activated or non-activated human Jurkat T lymphocytes (Figure 1, 2, 3)
Summary
Gravity has been a constant force throughout evolutionary history on Earth It is one of the fundamental biological questions, if and how life on Earth requires and responds to gravity at the functional cellular and molecular level. In unicellular organisms, such as Paramecium and Loxodes, gravity can be perceived rapidly by gravireceptors, which are gravi-sensitive ion channels in the cell membrane or statocyst-like organelles [1]. About one decade later, a pioneering discovery from Cogoli et al at the first Spacelab-Missions in the year 1983, where isolated human lymphocytes failed to proliferate after several days in microgravity, provided the first strong evidence of cell sensitivity to long-term reduced gravity exposure [8]. Follow-up experiments clearly verified the depression of lymphocyte proliferation activation after mitogenic stimulation in long-term microgravity [9]
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