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Granulocyte-monocyte progenitor cell cycle regulation occurs through calcium flux and calcineurin-NFAT signaling via Flt3-L

ABSTRACT: Complex regulatory mechanisms control continuous maintenance of myeloid progenitors and renewal of differentiated cells. Transcription factors play a important role in these processes. Here we report that the activation the calcineurin-NFAT signaling pathway inhibit the proliferation of myeloid granulocyte-monocyte progenitor (GMP). Myeloid progenitor subtypes possessed different susceptibilities to Ca2+ flux induction and consequently differential engagement of the calcineurin-NFAT pathway. This study show that inhibition of the calcineurin-NFAT pathway enhanced proliferation of GMPs both in vivo and in vitro. The calcineurin-NFAT signaling in GMPs is initiated through Flt3-L. The inhibition of the calcineurin-NFAT pathway altered the expression of the cell cycle regulation genes CDK4, CDK6, and CDKN1A, thus enabling faster cell cycle progression. The extensive use of NFAT inhibitors in the clinic should take into account that, in addition to the immunosuppression role in lymphoid cells, these NFAT inhibitors also affect the maintenance of the myeloid compartment. Microarray technology was used to understand the effects of NFAT inhibitors on C-kit enriched lineage negative cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE47208 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA205108

REPOSITORIES: GEO

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Calcineurin/NFAT signaling inhibits myeloid hematopoiesis in mice.

Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A. bone marrow cells from C57B/6 mice were stimulated in Flt3-L suplemented media in presence or absence of calcineurin/NFAT inhibitor Cyclosporin A, samples in 3 biological replicates

2011-09-30 | E-GEOD-29094 | biostudies-arrayexpress

Calcineurin/NFAT signaling inhibits myeloid hematopoiesis in mice.

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Calcineurin-NFAT signaling controls the neutrophils´ ability of chemoattraction upon fungal infection.

Project description:Calcineurin-nuclear factor of activated T-cell (CN-NFAT) inhibitors are widely clinically used drugs for immunosuppression but besides their required T-cell response inhibition, they also undesirably affect innate immune cells. Disruption of innate immune cell function can explain the observed susceptibility of CN-NFAT inhibitors-treated patients to opportunistic fungal infections. Neutrophils play a crucial role in the innate immunity pathogen defense, while however the effect of CN-NFAT inhibitors on neutrophil function is poorly described. Thus, we tested the response of human neutrophils to fungal pathogens, namely Candida albicans and Aspergillus fumigatus in the presence of CN-NFAT inhibitors. We report that the NFAT pathway members are expressed in neutrophils and mediates part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes. Importantly, genes involved in the regulation of the immune response and chemotaxis, including the chemokines CCL2 , CCL3, and CCL4 were significantly upregulated. The presence of CN-NFAT inhibitors attenuated the expression of these chemokines and impaired the ability of neutrophils to chemoattract other immune cells. Our results amend knowledge about the impact of CN-NFAT inhibition in human neutrophils.

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PHK Cells: control vs. cyclosporine vs. 11R-VIVIT

Project description:Calcineurin/NFAT signaling pathway has been shown to play important roles in various tissues such as the immune system, cardiac muscle and neuron. Although recent studies have shown that the pathway is involved in the regulation of hair growth, the precise mechanism is still unclear. In this study, we examine the molecular mechanism which is regulated by calcineurin/NFAT pathway, using two specific inhibitors for the pathway. Transcriptional profiling of human keratinocyte cell line, PHK cells, comparing control untreated PHK cells with cyclosporin A (CsA)-treated or 11R-VIVIT-treated PHK cells. Goal was to identify the effects of NFAT inhibitors on PHK cell proliferation. Cyclosporine A is a chemical compound, which strongly inhibits calcineurin phosphatase activity cooperating with cyclophilin, resulting in inhibition of NFAT signaling pathway. 11R-VIVIT is a cell-permeable peptide, which specifically interacts with NFAT and inhibits its binding to calcineurin, resulting in competitive inhibition of NFAT signaling pathway. Three-condition experiment; untreated PHK cells, CsA-treated PHK cells and 11R-VIVIT-treated PHK cells. Supplementary files: Significantly up-regulated genes across 4 different comparisons.

2010-11-08 | E-GEOD-25175 | biostudies-arrayexpress

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2010-07-15 | E-GEOD-21499 | biostudies-arrayexpress

PHK Cells: control vs. cyclosporine vs. 11R-VIVIT

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