Suppressed PHA activation of T lymphocytes in simulated microgravity is restored by direct activation of protein kinase C

Cooper, David A.; Pellis, Neal R.

doi:10.1002/jlb.63.5.550

Cited by 92 publications

(84 citation statements)

References 58 publications

(74 reference statements)

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“…during exposure of cells to microgravity has been proved by comparing data obtained in space experiments with those obtained in the RPM, as well as in other rotating devices [Cooper and Pellis, 1998;Schwarzenberg et al, 1999].…”

Section: Discussionmentioning

confidence: 99%

Modeled gravitational unloading triggers differentiation and apoptosis in preosteoclastic cells

et al. 2006

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Gravity acts permanently on organisms as either static or dynamic stimulation. Understanding the influence of gravitational and mechanical stimuli on biological systems is an intriguing scientific problem. More than two decades of life science studies in low g, either real or modeled by clinostats, as well as experimentation with devices simulating different types of controlled mechanical stimuli, have shown that important biological functions are altered at the single cell level. Here, we show that the human leukemic line FLG 29.1, characterized as an osteoclastic precursor model, is directly sensitive to gravitational unloading, modeled by a random positioning machine (RPM). The phenotypic expression of cytoskeletal proteins, osteoclastic markers, and factors regulating apoptosis was investigated using histochemical and immunohistochemical methods, while the expression of the corresponding genes was analyzed using RT-PCR. A quantitative bone resorption assay was performed. Autofluorescence spectroscopy and imaging were applied to gain information on cell metabolism. The results show that modeled hypogravity may trigger both differentiation and apoptosis in FLG 29.1 cells. Indeed, when comparing RPM versus 1 Â g cultures, in the former we found cytoskeletal alterations and a marked increase in apoptosis, but the surviving cells showed an osteoclastic-like morphology, overexpression of osteoclastic markers and the ability to resorb bone. In particular, the overexpression of both RANK and its ligand RANKL, maintained even after return to 1 Â g conditions, is consistent with the firing of a differentiation process via a paracrine/autocrine mechanism. J. Cell. Biochem. 98: 65-80, 2006. ß 2005 Wiley-Liss, Inc.Key words: weightlessness; preosteoclastic differentiation; apoptosis; bone resorption; osteoporosis; gene expressionThe importance of gravity in modulating some biological processes, such as plant gravitropism and the adaptation of the vertebrate skeleton in relation to its load-bearing function, has long been known. Nevertheless, the role of gravity and other mechanical factors in biological processes is far from clear. A weightless environment is a powerful tool for understanding this role and for studying the related cellular and molecular mechanisms. Several investigations conducted in space laboratories and with instruments averaging the gravity vector, and thus simulating conditions of reduced gravity, have shown that isolated cells may change their behavior under altered gravitational conditions. Loss of cell activation [Cogoli et al., 1984], perturbation of signal transduction [Schmitt et al., 1996;Hashemi et al., 1999] and modification of genetic expression [Walther et al., 1998;Hammond et al., 1999] have been described. This suggests that some of the mechanisms at the roots of the systemic effects observed in weightlessness, such as depression of the immune system [Gmü nder and Cogoli, 1996]

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Section: Discussionmentioning

confidence: 99%

Modeled gravitational unloading triggers differentiation and apoptosis in preosteoclastic cells

et al. 2006

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“…Others (9,10,19,23,24,34,43,89) have also noted marked suppression of IL-2 expression/secretion and responsiveness to phytohemagglutinin of T lymphocytes under microgravity conditions. However, this activation can be fully restored by direct activation of protein kinase C (PKC) with phorbal myristate acetate and ionomycin, agents that are able to bypass mechanisms at the cell surface and impart their effect inside the cell (PKC activation) (23,113). PKC and protein kinase A (PKA) are early regulators of T-cell activation (10).…”

Section: Immune System Cellsmentioning

confidence: 96%

“…In vitro clinostat analysis of mitogen-activated T lymphocytes revealed substantial decreases in IL-2 and IL-2 receptor gene expression in microgravity, thus inhibiting full T-cell activation (20,113). Others (9,10,19,23,24,34,43,89) have also noted marked suppression of IL-2 expression/secretion and responsiveness to phytohemagglutinin of T lymphocytes under microgravity conditions. However, this activation can be fully restored by direct activation of protein kinase C (PKC) with phorbal myristate acetate and ionomycin, agents that are able to bypass mechanisms at the cell surface and impart their effect inside the cell (PKC activation) (23,113).…”

Section: Immune System Cellsmentioning

confidence: 99%

“…Studies using groundbased models have demonstrated effects on immune system cells such as reduced activation/proliferation (113), altered cytokine production, and altered signal transduction (23). Spaceflight studies have also noted altered cytokine production (43), as well as altered distribution of peripheral immune cells (70).…”

Section: Immune System Cellsmentioning

confidence: 99%

“…PKC and protein kinase A (PKA) are early regulators of T-cell activation (10). Although some studies suggest that there may be a microgravity-induced PKC defect (19,27,94), the impairment in the T-cell activation process has been found to be upstream of PKC activation (23,113). However, the translocation of individual PKC isoforms ␤ II, ␦, and ⑀ is differentially altered under microgravity (40, 46).…”

Section: Immune System Cellsmentioning

confidence: 99%

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Proteomics and genomics of microgravity

Nichols

Zhang

Wen

2006

Physiological Genomics

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Many serious adverse physiological changes occur during spaceflight. In the search for underlying mechanisms and possible new countermeasures, many experimental tools and methods have been developed to study microgravity caused physiological changes, ranging from in vitro bioreactor studies to spaceflight investigations. Recently, genomic and proteomic approaches have gained a lot of attention; after major scientific breakthroughs in the fields of genomics and proteomics, they are now widely accepted and used to understand biological processes. Understanding gene and/or protein expression is the key to unfolding the mechanisms behind microgravity-induced problems and, ultimately, finding effective countermeasures to spaceflight-induced alterations. Significant progress has been made in identifying the genes/proteins responsible for these changes. Although many of these genes and/or proteins were observed to be either upregulated or downregulated, however, no large-scale genomics and proteomics studies have been published so far. This review aims at summarizing the current status of microgravity-related genomics and proteomics studies and stimulating large-scale proteomics and genomics research activities.

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Regulation of heat shock protein message in Jurkat cells cultured under serum-starved and gravity-altered conditions

Lewis

Hughes‐Fulford

2000

J. Cell. Biochem.

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Although our understanding of effects of space flight on human physiology has advanced significantly over the past four decades, the potential contribution of stress at the cellular and gene regulation level is not characterized. The objective of this ground-based study was to evaluate stress gene regulation in cells exposed to altered gravity and environmentally suboptimal conditions. We designed primers to detect message for both the constitutive and inducible forms of the heat shock protein, HSP-70. Applying the reverse transcriptase-polymerase chain reaction (RT-PCR), we probed for HSP-70 message in human acute T-cell leukemia cells, Jurkat, subjected to three types of environmental stressors: (1) altered gravity achieved by centrifugation (hypergravity) and randomization of the gravity vector in rotating bioreactors, (2) serum starvation by culture in medium containing 0.05% serum, and (3) temperature elevation (42 degrees C). Temperature elevation, as the positive control, significantly increased HSP-70 message, while centrifugation and culture in rotating bioreactors did not upregulate heat shock gene expression. We found a fourfold increase in heat shock message in serum-starved cells. Message for the housekeeping genes, actin and cyclophilin, were constant and comparable to unstressed controls for all treatments. We conclude that gravitational perturbations incurred by centrifugal forces, exceeding those characteristic of a Space Shuttle launch (3g), and culture in rotating bioreactors do not upregulate HSP-70 gene expression. In addition, we found RT-PCR useful for evaluating stress in cultured cells.

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Suppressed PHA activation of T lymphocytes in simulated microgravity is restored by direct activation of protein kinase C

Cited by 92 publications

References 58 publications

Modeled gravitational unloading triggers differentiation and apoptosis in preosteoclastic cells

Modeled gravitational unloading triggers differentiation and apoptosis in preosteoclastic cells

Proteomics and genomics of microgravity

Regulation of heat shock protein message in Jurkat cells cultured under serum-starved and gravity-altered conditions

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