D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells
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 myel...
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MDPI AG
2019-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/20/3/742 |
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| author | Ines Ugele Zugey Elizabeth Cárdenas-Conejo Kathrin Hammon Monika Wehrstein Christina Bruss Katrin Peter Katrin Singer Eva Gottfried Jakob Boesch Peter Oefner Katja Dettmer Kathrin Renner Marina Kreutz |
| author_facet | Ines Ugele Zugey Elizabeth Cárdenas-Conejo Kathrin Hammon Monika Wehrstein Christina Bruss Katrin Peter Katrin Singer Eva Gottfried Jakob Boesch Peter Oefner Katja Dettmer Kathrin Renner Marina Kreutz |
| author_sort | Ines Ugele |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T07:15:40Z |
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| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-13T07:15:40Z |
| publishDate | 2019-02-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-71614b3a027c46b482c42d297ff174212022-12-22T02:56:45ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-02-0120374210.3390/ijms20030742ijms20030742D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic CellsInes Ugele0Zugey Elizabeth Cárdenas-Conejo1Kathrin Hammon2Monika Wehrstein3Christina Bruss4Katrin Peter5Katrin Singer6Eva Gottfried7Jakob Boesch8Peter Oefner9Katja Dettmer10Kathrin Renner11Marina Kreutz12Ear, Nose and Throat Department, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyInstitute of Functional Genomics, University of Regensburg, Regensburg 93053, GermanyInstitute of Functional Genomics, University of Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg 93053, GermanyMutations 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.https://www.mdpi.com/1422-0067/20/3/742isocitrate dehydrogenasehydroxyglutaratedendritic cellstumor environmentactivation |
| spellingShingle | Ines Ugele Zugey Elizabeth Cárdenas-Conejo Kathrin Hammon Monika Wehrstein Christina Bruss Katrin Peter Katrin Singer Eva Gottfried Jakob Boesch Peter Oefner Katja Dettmer Kathrin Renner Marina Kreutz D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells International Journal of Molecular Sciences isocitrate dehydrogenase hydroxyglutarate dendritic cells tumor environment activation |
| title | D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells |
| title_full | D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells |
| title_fullStr | D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells |
| title_full_unstemmed | D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells |
| title_short | D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells |
| title_sort | d 2 hydroxyglutarate and l 2 hydroxyglutarate inhibit il 12 secretion by human monocyte derived dendritic cells |
| topic | isocitrate dehydrogenase hydroxyglutarate dendritic cells tumor environment activation |
| url | https://www.mdpi.com/1422-0067/20/3/742 |
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