The Journal of immunology (1950), 2013-05, Vol.190 (9), p.4640-4649
2013
Details
- Autor(en) / Beteiligte
- Titel
- Role of fatty-acid synthesis in dendritic cell generation and function
- Ist Teil von
- The Journal of immunology (1950), 2013-05, Vol.190 (9), p.4640-4649
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- Electronic Journals Library
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-1767eISSN: 1550-6606DOI: 10.4049/jimmunol.1202312Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3633656
- Format
- –
- Schlagworte
- Animals, Apoptosis - immunology, B7-1 Antigen - immunology, B7-1 Antigen - metabolism, B7-2 Antigen - immunology, B7-2 Antigen - metabolism, bcl-X Protein - immunology, bcl-X Protein - metabolism, Caspase 3 - immunology, Caspase 3 - metabolism, CD4-Positive T-Lymphocytes - immunology, CD4-Positive T-Lymphocytes - metabolism, CD8-Positive T-Lymphocytes - immunology, CD8-Positive T-Lymphocytes - metabolism, Cell Differentiation - immunology, Chemokine CCL2 - immunology, Chemokine CCL2 - metabolism, Cyclin B1 - immunology, Cyclin B1 - metabolism, Dendritic Cells - cytology, Dendritic Cells - immunology, Dendritic Cells - metabolism, Endoplasmic Reticulum - immunology, Endoplasmic Reticulum - metabolism, Fatty Acids - biosynthesis, Fatty Acids - immunology, Fatty Acids - metabolism, Genes, MHC Class II - immunology, Humans, Intercellular Adhesion Molecule-1 - immunology, Intercellular Adhesion Molecule-1 - metabolism, Interferon-gamma - immunology, Interferon-gamma - metabolism, Interleukin-12 - immunology, Interleukin-12 - metabolism, Killer Cells, Natural - immunology, Killer Cells, Natural - metabolism, Leukocytes, Mononuclear - immunology, Leukocytes, Mononuclear - metabolism, Liver - immunology, Liver - metabolism, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase Kinases - immunology, Mitogen-Activated Protein Kinase Kinases - metabolism, PPAR gamma - immunology, PPAR gamma - metabolism, Proto-Oncogene Proteins c-akt - immunology, Proto-Oncogene Proteins c-akt - metabolism, T-Lymphocytes, Cytotoxic - immunology, T-Lymphocytes, Cytotoxic - metabolism