PMID- 30463908 OWN - NLM STAT- MEDLINE DCOM- 20190729 LR - 20220129 IS - 1573-4935 (Electronic) IS - 0144-8463 (Print) IS - 0144-8463 (Linking) VI - 38 IP - 6 DP - 2018 Dec 21 TI - Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor alpha via MAP3K8. LID - BSR20182019 [pii] LID - 10.1042/BSR20182019 [doi] AB - Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-alpha secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved. CI - (c) 2018 The Author(s). FAU - Paardekooper, Laurent M AU - Paardekooper LM AUID- ORCID: 0000-0001-7079-2697 AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Bendix, Maura B AU - Bendix MB AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Ottria, Andrea AU - Ottria A AD - Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht. AD - Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht. FAU - de Haer, Lieke W AU - de Haer LW AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Ter Beest, Martin AU - Ter Beest M AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Radstake, Timothy R D J AU - Radstake TRDJ AD - Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht. AD - Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht. FAU - Marut, Wioleta AU - Marut W AD - Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht. AD - Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht. FAU - van den Bogaart, Geert AU - van den Bogaart G AUID- ORCID: 0000-0003-2180-6735 AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands g.van.den.bogaart@rug.nl. AD - Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands. LA - eng GR - 336479/ERC_/European Research Council/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181214 PL - England TA - Biosci Rep JT - Bioscience reports JID - 8102797 RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (TLR4 protein, human) RN - 0 (TNF protein, human) RN - 0 (Toll-Like Receptor 4) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - EC 2.7.11.25 (MAP3K8 protein, human) MH - Cell Hypoxia MH - Cells, Cultured MH - Dendritic Cells/cytology/*immunology/metabolism MH - Humans MH - Hypoxia/genetics/*immunology MH - Inflammation/genetics/*immunology MH - MAP Kinase Kinase Kinases/genetics/*immunology MH - Monocytes/cytology MH - Proto-Oncogene Proteins/genetics/*immunology MH - RNA Interference MH - RNA, Small Interfering/genetics MH - Toll-Like Receptor 4/immunology MH - Tumor Necrosis Factor-alpha/*immunology MH - Up-Regulation PMC - PMC6294625 OTO - NOTNLM OT - dendritic cells OT - hypoxia OT - inflammation OT - mitogen-activated protein kinases OT - tumour necrosis factors COIS- The authors declare that there are no competing interests associated with the manuscript. EDAT- 2018/11/23 06:00 MHDA- 2019/07/30 06:00 PMCR- 2018/12/14 CRDT- 2018/11/23 06:00 PHST- 2018/10/04 00:00 [received] PHST- 2018/11/20 00:00 [revised] PHST- 2018/11/20 00:00 [accepted] PHST- 2018/11/23 06:00 [pubmed] PHST- 2019/07/30 06:00 [medline] PHST- 2018/11/23 06:00 [entrez] PHST- 2018/12/14 00:00 [pmc-release] AID - BSR20182019 [pii] AID - 10.1042/BSR20182019 [doi] PST - epublish SO - Biosci Rep. 2018 Dec 14;38(6):BSR20182019. doi: 10.1042/BSR20182019. Print 2018 Dec 21.