D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells
D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells
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DOI：
10.3390/ijms20030742
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Kreutz, Marina
中科院分区：
文献类型：
--
作者：
Ugele, Ines;Cardenas-Conejo, Zugey Elizabeth;Kreutz, Marina
异柠檬酸脱氢酶（IDH）的突变或L-2-羟基戊二酸（HG）-脱氢酶表达的降低分别导致D-2-HG或L-2-HG在肿瘤组织中的积累。D-2-HG和L-2-HG已显示影响T细胞分化和活化;然而，迄今为止尚未研究对人骨髓细胞的影响。在这项研究中，我们分析了D-2-HG和L-2-HG对人单核细胞来源的树突状细胞（DC）的活化和成熟的影响。2-HG被DC摄取，并且对细胞活力没有影响，但在脂多糖（LPS）刺激后降低了CD 83表达。此外，D-2-HG和L-2-HG显著降低IL-12的分泌，但对其他细胞因子如IL-6、IL-10或TNF没有影响。IL-12亚基p35/IL-12 A和p40/IL-12 B在DC中的基因表达分析显示两种亚基的表达降低。参与LPS诱导的细胞因子表达（NF κ B，Akt，p38）的信号通路没有被D-2-HG改变。然而，2-HG重编程LPS诱导的DC代谢变化和增加耗氧量。添加ATP合成酶抑制剂寡霉素的DC培养物增加IL-12的分泌，并能够部分逆转2-HG的效果。我们的数据表明，2-HG的两种对映体都可以限制肿瘤环境中DC的活化。
Mutations in isocitrate dehydrogenase (IDH) or a reduced expression of L-2-hydroxyglutarate (HG)-dehydrogenase result in accumulation of D-2-HG or L-2-HG, respectively, in tumor tissues. D-2-HG and L-2-HG have been shown to affect T-cell differentiation and activation; however, effects on human myeloid cells have not been investigated so far. In this study we analyzed the impact of D-2-HG and L-2-HG on activation and maturation of human monocyte-derived dendritic cells (DCs). 2-HG was taken up by DCs and had no impact on cell viability but diminished CD83 expression after Lipopolysaccharides (LPS) stimulation. Furthermore, D-2-HG and L-2-HG significantly reduced IL-12 secretion but had no impact on other cytokines such as IL-6, IL-10 or TNF. Gene expression analyses of the IL-12 subunits p35/IL-12A and p40/IL-12B in DCs revealed decreased expression of both subunits. Signaling pathways involved in LPS-induced cytokine expression (NFkB, Akt, p38) were not altered by D-2-HG. However, 2-HG reprogrammed LPS-induced metabolic changes in DCs and increased oxygen consumption. Addition of the ATP synthase inhibitor oligomycin to DC cultures increased IL-12 secretion and was able to partially revert the effect of 2-HG. Our data show that both enantiomers of 2-HG can limit activation of DCs in the tumor environment.