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Int. J. Mol. Sci. 2019, 20(3), 742; https://doi.org/10.3390/ijms20030742

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

1
Ear, Nose and Throat Department, University Hospital Regensburg, Regensburg 93053, Germany
2
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany
3
Institute of Functional Genomics, University of Regensburg, Regensburg 93053, Germany
4
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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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. 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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