Ugele, Ines and Cardenas-Conejo, Zugey Elizabeth and Hammon, Kathrin and Wehrstein, Monika and Bruss, Christina and Peter, Katrin and Singer, Katrin and Gottfried, Eva and Boesch, Jakob and Oefner, Peter and Dettmer, Katja and Renner, Kathrin and Kreutz, Marina (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): 742. ISSN 1422-0067,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; LACTIC-ACID; PROGNOSTIC-SIGNIFICANCE; IDH MUTATION; MACROPHAGES; MITOCHONDRIAL; METABOLISM; SURVIVAL; KINASE; INFILTRATION; isocitrate dehydrogenase; hydroxyglutarate; dendritic cells; tumor environment; activation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Hals-Nasen-Ohren-Heilkunde Medicine > Lehrstuhl für Immunologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Apr 2020 06:51 |
| Last Modified: | 22 Apr 2020 06:51 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27591 |
Actions (login required)
 |
View Item |
