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Int. J. Mol. Sci. 2019, 20(3), 742;

D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells

Ear, Nose and Throat Department, University Hospital Regensburg, Regensburg 93053, Germany
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany
Institute of Functional Genomics, University of Regensburg, Regensburg 93053, Germany
Regensburg Center for Interventional Immunology, Regensburg, Regensburg 93053, Germany
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 10 January 2019 / Revised: 1 February 2019 / Accepted: 5 February 2019 / Published: 10 February 2019
(This article belongs to the Special Issue Tumor Microenvironment 2019)
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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. View Full-Text
Keywords: isocitrate dehydrogenase; hydroxyglutarate; dendritic cells; tumor environment; activation isocitrate dehydrogenase; hydroxyglutarate; dendritic cells; tumor environment; activation

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Ugele, I.; Cárdenas-Conejo, Z.E.; Hammon, K.; Wehrstein, M.; Bruss, C.; Peter, K.; Singer, K.; Gottfried, E.; Boesch, J.; Oefner, P.; Dettmer, K.; Renner, K.; Kreutz, M. D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells. Int. J. Mol. Sci. 2019, 20, 742.

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