We are analyzing https://link.springer.com/article/10.1186/1471-2121-13-18.

Title:
Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models | BMC Molecular and Cell Biology
Description:
Background The tumor microenvironment contains a vast array of pro- and anti-inflammatory cytokines that alter myelopoiesis and lead to the maturation of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Incubating bone marrow (BM) precursors with a combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) generated a tumor-infiltrating MDSC-like population that impaired anti-tumor specific T-cell functions. This in vitro experimental approach was used to simulate MDSC maturation, and the cellular metabolic response was then monitored. A complementary experimental model that inhibited L-arginine (L-Arg) metabolizing enzymes in MSC-1 cells, an immortalized cell line derived from primary MDSCs, was used to study the metabolic events related to immunosuppression. Results Exposure of BM cells to GM-CSF and IL-6 activated, within 24 h, L-Arg metabolizing enzymes which are responsible for the MDSCs immunosuppressive potential. This was accompanied by an increased uptake of L-glutamine (L-Gln) and glucose, the latter being metabolized by anaerobic glycolysis. The up-regulation of nutrient uptake lead to the accumulation of TCA cycle intermediates and lactate as well as the endogenous synthesis of L-Arg and the production of energy-rich nucleotides. Moreover, inhibition of L-Arg metabolism in MSC-1 cells down-regulated central carbon metabolism activity, including glycolysis, glutaminolysis and TCA cycle activity, and led to a deterioration of cell bioenergetic status. The simultaneous increase of cell specific concentrations of ATP and a decrease in ATP-to-ADP ratio in BM-derived MDSCs suggested cells were metabolically active during maturation. Moreover, AMP-activated protein kinase (AMPK) was activated during MDSC maturation in GM-CSF and IL-6–treated cultures, as revealed by the continuous increase of AMP-to-ATP ratios and the phosphorylation of AMPK. Likewise, AMPK activity was decreased in MSC-1 cells when L-Arg metabolizing enzymes were inhibited. Finally, inhibition of AMPK activity by the specific inhibitor Compound C (Comp-C) resulted in the inhibition of L-Arg metabolizing enzyme activity and abolished MDSCs immunosuppressive activity. Conclusions We anticipate that the inhibition of AMPK and the control of metabolic fluxes may be considered as a novel therapeutic target for the recovery of the immunosurveillance process in cancer-bearing hosts.
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Keywords {🔍}

cells, cell, activity, culture, figure, mdscs, ampk, article, arg, bmderived, pubmed, inos, google, scholar, msc, gmcsf, specific, cas, rate, control, inhibition, min, metabolism, glucose, immunosuppressive, maturation, mdsc, jurkat, presence, production, increased, atp, energy, ratio, central, viability, larg, uptake, concentrations, growth, metabolic, glycolysis, cycle, activation, concentration, suppressor, accumulation, tca, compc, expression,

Topics {✒️}

cytokine-treated comp-c-pre-treated bm-cells mitogen-activated protein kinase granulocyte-macrophage colony-stimulating factor inducible nitric-oxide synthase open access article amp-activated protein kinase 5'-amp-activated protein kinase granulocyte colony-stimulating factor comp-c-related side effects mentioned uplc-ms/ms system myeloid-derived suppressor cells downstream-activated signaling pathways central carbon metabolism nadp+−dependent 'malic' enzyme article download pdf nitric oxide synthase ccaat-enhancer-binding protein hypoxia-inducible factor hydrogen peroxide-dependent mechanisms bm-derived mdscs exhibit tumor-derived soluble factors nucleotide-derived behavioral biomarkers pre-treated bm cells msc-1 cells pre-treated bm-derived mdsc cultures uplc-ms/ms system specific pathogen-free conditions nucleotide-derived biomarkers showed security c18 guard-column partially oxidize l-gln myeloid suppressor cells-1 myeloid suppressor cells hif-1alpha regulates function cytokine-related cytotoxic effects bm-derived mdscs cultures nucleotide-derived behavioral markers bm-derived mdsc culture msc-1 cells pre-cultured immunosuppression-related energy demand bm-derived mdsc extracts detached bm-derived mdscs nitric oxide concentrations bm-derived mdsc maturation quasi-hypoxic conditions encountered il-6-treated bm cells bone marrow-derived cells glucose-derived carbon hif-1α transcriptional activity l-arg metabolizing enzymes inhibited antigen-specific proliferation

Questions {❓}

Gatenby RA, Gillies RJ: Why do cancers have high aerobic glycolysis?

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WebPage:
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         headline:Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models
         description:The tumor microenvironment contains a vast array of pro- and anti-inflammatory cytokines that alter myelopoiesis and lead to the maturation of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Incubating bone marrow (BM) precursors with a combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) generated a tumor-infiltrating MDSC-like population that impaired anti-tumor specific T-cell functions. This in vitro experimental approach was used to simulate MDSC maturation, and the cellular metabolic response was then monitored. A complementary experimental model that inhibited L-arginine (L-Arg) metabolizing enzymes in MSC-1 cells, an immortalized cell line derived from primary MDSCs, was used to study the metabolic events related to immunosuppression. Exposure of BM cells to GM-CSF and IL-6 activated, within 24 h, L-Arg metabolizing enzymes which are responsible for the MDSCs immunosuppressive potential. This was accompanied by an increased uptake of L-glutamine (L-Gln) and glucose, the latter being metabolized by anaerobic glycolysis. The up-regulation of nutrient uptake lead to the accumulation of TCA cycle intermediates and lactate as well as the endogenous synthesis of L-Arg and the production of energy-rich nucleotides. Moreover, inhibition of L-Arg metabolism in MSC-1 cells down-regulated central carbon metabolism activity, including glycolysis, glutaminolysis and TCA cycle activity, and led to a deterioration of cell bioenergetic status. The simultaneous increase of cell specific concentrations of ATP and a decrease in ATP-to-ADP ratio in BM-derived MDSCs suggested cells were metabolically active during maturation. Moreover, AMP-activated protein kinase (AMPK) was activated during MDSC maturation in GM-CSF and IL-6–treated cultures, as revealed by the continuous increase of AMP-to-ATP ratios and the phosphorylation of AMPK. Likewise, AMPK activity was decreased in MSC-1 cells when L-Arg metabolizing enzymes were inhibited. Finally, inhibition of AMPK activity by the specific inhibitor Compound C (Comp-C) resulted in the inhibition of L-Arg metabolizing enzyme activity and abolished MDSCs immunosuppressive activity. We anticipate that the inhibition of AMPK and the control of metabolic fluxes may be considered as a novel therapeutic target for the recovery of the immunosurveillance process in cancer-bearing hosts.
         datePublished:2012-07-04T00:00:00Z
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            Biological Microscopy
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      headline:Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models
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         Myeloid-derived suppressor cells
         GM-CSF
         IL-6
         MSC-1 cells
         Central carbon metabolism
         Bioenergetics
         Cell Biology
         Biological Microscopy
         Life Sciences
         general
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            name:Ecole Polytechnique de Montréal
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               type:PostalAddress
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      name:Department of Pathology, Immunology Section, Verona University, Verona, Italy
      name:Department of Chemical Engineering, Ecole Polytechnique de Montréal, Montreal, Canada
      name:Department of Chemical Engineering, Ecole Polytechnique de Montréal, Montreal, Canada

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