D-2-hydroxyglutarate and L-2-hydroxyglutarate inhibit IL-12 secretion by human monocyte-derived dendritic cells
Ugele I, Cardenas-Conejo ZE, Hammon K, Wehrstein M, Bruss C, Peter K, Singer K, Gottfried E, Boesch J, Oefner P, Dettmer K, Renner K, Kreutz M (2019)
Publication Type: Journal article
Publication year: 2019
Journal
Book Volume: 20
Article Number: 742
Journal Issue: 3
DOI: 10.3390/ijms20030742
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.
Involved external institutions
Germany (DE)How to cite
APA:
Ugele, I., Cardenas-Conejo, Z.E., Hammon, K., Wehrstein, M., Bruss, C., Peter, K.,... Kreutz, M. (2019). D-2-hydroxyglutarate and L-2-hydroxyglutarate inhibit IL-12 secretion by human monocyte-derived dendritic cells. International Journal of Molecular Sciences, 20(3). https://doi.org/10.3390/ijms20030742
MLA:
Ugele, Ines, et al. "D-2-hydroxyglutarate and L-2-hydroxyglutarate inhibit IL-12 secretion by human monocyte-derived dendritic cells." International Journal of Molecular Sciences 20.3 (2019).
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