Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4
Dendritic cell (DC)-based immunotherapy makes use of the DC’s ability to direct the adaptive immune response toward activation or inhibition. DCs perform this immune orchestration in part by secretion of selected cytokines. The most potent anti-inflammatory cytokine interleukin-10 (IL-10) is under t...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-06-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01420/full |
| _version_ | 1819089141157068800 |
|---|---|
| author | Jonas Nørskov Søndergaard Simon J. van Heeringen Maaike W. G. Looman Chunling Tang Vassilis Triantis Pauline Louche Eva M. Janssen-Megens Anieta M. Sieuwerts John W. M. Martens Colin Logie Hendrik G. Stunnenberg Marleen Ansems Gosse J. Adema |
| author_facet | Jonas Nørskov Søndergaard Simon J. van Heeringen Maaike W. G. Looman Chunling Tang Vassilis Triantis Pauline Louche Eva M. Janssen-Megens Anieta M. Sieuwerts John W. M. Martens Colin Logie Hendrik G. Stunnenberg Marleen Ansems Gosse J. Adema |
| author_sort | Jonas Nørskov Søndergaard |
| collection | DOAJ |
| description | Dendritic cell (DC)-based immunotherapy makes use of the DC’s ability to direct the adaptive immune response toward activation or inhibition. DCs perform this immune orchestration in part by secretion of selected cytokines. The most potent anti-inflammatory cytokine interleukin-10 (IL-10) is under tight regulation, as it needs to be predominantly expressed during the resolution phase of the immune response. Currently it is not clear whether there is active suppression of IL-10 by DCs at the initial pro-inflammatory stage of the immune response. Previously, knockdown of the DC-specific transcription factor DC-SCRIPT has been demonstrated to mediate an extensive increase in IL-10 production upon encounter with pro-inflammatory immune stimuli. Here, we explored how DC-SCRIPT contributes to IL-10 suppression under pro-inflammatory conditions by applying chromatin immunoprecipitation sequencing analysis of DC-SCRIPT and the epigenetic marks H3K4me3 and H3K27ac in human DCs. The data showed binding of DC-SCRIPT to a GA-rich motif at H3K27ac-marked genomic enhancers that associated with genes encoding MAPK dual-specificity phosphatases (DUSPs). Functional studies revealed that upon knockdown of DC-SCRIPT, human DCs express much less DUSP4 and exhibit increased phosphorylation of the three major MAPKs (ERK, JNK, and p38). Enhanced ERK signaling in DC-SCRIPT-knockdown-DCs led to higher production of IL-10, which was reverted by rescuing DUSP4 expression. Finally, DC-SCRIPT-knockdown-DCs induced less IFN-γ and increased IL-10 production in naïve T cells, indicative for a more anti-inflammatory phenotype. In conclusion, we have delineated a new mechanism by which DC-SCRIPT allows DCs to limit IL-10 production under inflammatory conditions and potentiate pro-inflammatory Th1 responses. These insights may be exploited to improve DC-based immunotherapies. |
| first_indexed | 2024-12-21T22:03:13Z |
| format | Article |
| id | doaj.art-ddbaab4a79cd4ec38bc9f51fd0f60db0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T22:03:13Z |
| publishDate | 2018-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ddbaab4a79cd4ec38bc9f51fd0f60db02022-12-21T18:48:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-06-01910.3389/fimmu.2018.01420386444Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4Jonas Nørskov Søndergaard0Simon J. van Heeringen1Maaike W. G. Looman2Chunling Tang3Vassilis Triantis4Pauline Louche5Eva M. Janssen-Megens6Anieta M. Sieuwerts7John W. M. Martens8Colin Logie9Hendrik G. Stunnenberg10Marleen Ansems11Gosse J. Adema12Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, NetherlandsRadiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsRadiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsRadiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsRadiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, NetherlandsDepartment of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, NetherlandsDepartment of Molecular Biology, Faculties of Science and Medicine, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, NetherlandsRadiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsRadiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDendritic cell (DC)-based immunotherapy makes use of the DC’s ability to direct the adaptive immune response toward activation or inhibition. DCs perform this immune orchestration in part by secretion of selected cytokines. The most potent anti-inflammatory cytokine interleukin-10 (IL-10) is under tight regulation, as it needs to be predominantly expressed during the resolution phase of the immune response. Currently it is not clear whether there is active suppression of IL-10 by DCs at the initial pro-inflammatory stage of the immune response. Previously, knockdown of the DC-specific transcription factor DC-SCRIPT has been demonstrated to mediate an extensive increase in IL-10 production upon encounter with pro-inflammatory immune stimuli. Here, we explored how DC-SCRIPT contributes to IL-10 suppression under pro-inflammatory conditions by applying chromatin immunoprecipitation sequencing analysis of DC-SCRIPT and the epigenetic marks H3K4me3 and H3K27ac in human DCs. The data showed binding of DC-SCRIPT to a GA-rich motif at H3K27ac-marked genomic enhancers that associated with genes encoding MAPK dual-specificity phosphatases (DUSPs). Functional studies revealed that upon knockdown of DC-SCRIPT, human DCs express much less DUSP4 and exhibit increased phosphorylation of the three major MAPKs (ERK, JNK, and p38). Enhanced ERK signaling in DC-SCRIPT-knockdown-DCs led to higher production of IL-10, which was reverted by rescuing DUSP4 expression. Finally, DC-SCRIPT-knockdown-DCs induced less IFN-γ and increased IL-10 production in naïve T cells, indicative for a more anti-inflammatory phenotype. In conclusion, we have delineated a new mechanism by which DC-SCRIPT allows DCs to limit IL-10 production under inflammatory conditions and potentiate pro-inflammatory Th1 responses. These insights may be exploited to improve DC-based immunotherapies.https://www.frontiersin.org/article/10.3389/fimmu.2018.01420/fullZNF366ERKchromatin immunoprecipitation sequencingdual-specificity phosphatase 4dendritic cellsMAPK |
| spellingShingle | Jonas Nørskov Søndergaard Simon J. van Heeringen Maaike W. G. Looman Chunling Tang Vassilis Triantis Pauline Louche Eva M. Janssen-Megens Anieta M. Sieuwerts John W. M. Martens Colin Logie Hendrik G. Stunnenberg Marleen Ansems Gosse J. Adema Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4 Frontiers in Immunology ZNF366 ERK chromatin immunoprecipitation sequencing dual-specificity phosphatase 4 dendritic cells MAPK |
| title | Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4 |
| title_full | Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4 |
| title_fullStr | Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4 |
| title_full_unstemmed | Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4 |
| title_short | Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4 |
| title_sort | dendritic cells actively limit interleukin 10 production under inflammatory conditions via dc script and dual specificity phosphatase 4 |
| topic | ZNF366 ERK chromatin immunoprecipitation sequencing dual-specificity phosphatase 4 dendritic cells MAPK |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.01420/full |
| work_keys_str_mv | AT jonasnørskovsøndergaard dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT simonjvanheeringen dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT maaikewglooman dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT chunlingtang dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT vassilistriantis dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT paulinelouche dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT evamjanssenmegens dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT anietamsieuwerts dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT johnwmmartens dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT colinlogie dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT hendrikgstunnenberg dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT marleenansems dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 AT gossejadema dendriticcellsactivelylimitinterleukin10productionunderinflammatoryconditionsviadcscriptanddualspecificityphosphatase4 |