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- Title
D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells.
- Authors
Ugele, Ines; Cárdenas-Conejo, Zugey Elizabeth; Hammon, Kathrin; Wehrstein, Monika; Bruss, Christina; Peter, Katrin; Singer, Katrin; Gottfried, Eva; Boesch, Jakob; Oefner, Peter; Dettmer, Katja; Renner, Kathrin; Kreutz, Marina
- Abstract
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.
- Subjects
ISOCITRATE dehydrogenase; GENETIC mutation; DENDRITIC cells; GENE expression; CELL differentiation; LIPOPOLYSACCHARIDES
- Publication
International Journal of Molecular Sciences, 2019, Vol 20, Issue 3, p742
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms20030742