Role of fatty-acid synthesis in dendritic cell generation and function.
Role of fatty-acid synthesis in dendritic cell generation and function.
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DOI：
10.4049/jimmunol.1202312
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Miller G
中科院分区：
文献类型：
--
作者：
Rehman A;Hemmert KC;Ochi A;Jamal M;Henning JR;Barilla R;Quesada JP;Zambirinis CP;Tang K;Ego-Osuala M;Rao RS;Greco S;Deutsch M;Narayan S;Pachter HL;Graffeo CS;Acehan D;Miller G
Dendritic cells (DC) are professional antigen presenting cells 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 down-regulation of Cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHCII, ICAM-1, B7-1, B7-2 but increased their production of selected pro-inflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacityto activate allogeneic as well as antigen-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. Since endoplasmic reticular (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 MAP kinase 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.
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影响因子：
6.5
作者：
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通讯作者：
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通讯作者：
Miller G
DOI：
10.1073/pnas.1011736107
发表时间：
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影响因子：
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