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Int J Mol Sci. 2019 Feb 10;20(3). pii: E742. doi: 10.3390/ijms20030742.

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

Author information

1
Ear, Nose and Throat Department, University Hospital Regensburg, Regensburg 93053, Germany. ines.ugele@ukr.de.
2
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. elizabeth_cardenas_86@outlook.com.
3
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. Kathrin.Hammon@ukr.de.
4
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. monika.wehrstein@ukr.de.
5
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. christina.bruss@ukr.de.
6
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. katrin.peter@ukr.de.
7
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. katrin.singer@ukr.de.
8
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. eva.gottfried@gmx.de.
9
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. jakobboesch@icloud.com.
10
Institute of Functional Genomics, University of Regensburg, Regensburg 93053, Germany. Peter.Oefner@klinik.uni-regensburg.de.
11
Institute of Functional Genomics, University of Regensburg, Regensburg 93053, Germany. Katja.Dettmer@klinik.uni-regensburg.de.
12
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. Kathrin.Renner-Sattler@klinik.uni-regensburg.de.
13
Regensburg Center for Interventional Immunology, Regensburg, Regensburg 93053, Germany. Kathrin.Renner-Sattler@klinik.uni-regensburg.de.
14
Department of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, Germany. marina.kreutz@ukr.de.
15
Regensburg Center for Interventional Immunology, Regensburg, Regensburg 93053, Germany. marina.kreutz@ukr.de.

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.

KEYWORDS:

activation; dendritic cells; hydroxyglutarate; isocitrate dehydrogenase; tumor environment

PMID:
30744183
PMCID:
PMC6387367
DOI:
10.3390/ijms20030742
[Indexed for MEDLINE]
Free PMC Article

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