Abstract
Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4(+) and CD8(+) T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis / immunology
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B7-1 Antigen / immunology
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B7-1 Antigen / metabolism
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B7-2 Antigen / immunology
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B7-2 Antigen / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Caspase 3 / immunology
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Caspase 3 / metabolism
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Cell Differentiation / immunology*
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Chemokine CCL2 / immunology
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Chemokine CCL2 / metabolism
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Cyclin B1 / immunology
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Cyclin B1 / metabolism
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Endoplasmic Reticulum / immunology
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Endoplasmic Reticulum / metabolism
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Fatty Acids / biosynthesis*
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Fatty Acids / immunology
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Fatty Acids / metabolism
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Genes, MHC Class II / immunology
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Humans
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Intercellular Adhesion Molecule-1 / immunology
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Intercellular Adhesion Molecule-1 / metabolism
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Liver / immunology
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Liver / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase Kinases / immunology
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Mitogen-Activated Protein Kinase Kinases / metabolism
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PPAR gamma / immunology
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PPAR gamma / metabolism
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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bcl-X Protein / immunology
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bcl-X Protein / metabolism
Substances
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B7-1 Antigen
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B7-2 Antigen
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Chemokine CCL2
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Cyclin B1
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Fatty Acids
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PPAR gamma
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bcl-X Protein
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Intercellular Adhesion Molecule-1
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Interleukin-12
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Interferon-gamma
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase Kinases
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Caspase 3