Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells
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Open Access
- 17 November 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 118 (20), 5498-5505
- https://doi.org/10.1182/blood-2011-07-365825
Abstract
Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2), the key regulator of PGE2 synthesis, represents the determining factor in redirecting the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs. Exogenous PGE2 and such diverse COX2 activators as lipopolysaccharide, IL-1β, and IFNγ all induce monocyte expression of COX2, blocking their differentiation into CD1a+ DCs and inducing endogenous PGE2, IDO1, IL-4Rα, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE2 to GM-CSF/IL-4–supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)–suppressive function. In accordance with the key role of PGE2 in the physiologic induction of human MDSCs, the frequencies of CD11b+CD33+ MDSCs in ovarian cancer are closely correlated with local PGE2 production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE2 feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients. The central role of COX2-PGE2 feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity, or transplantation.Keywords
This publication has 52 references indexed in Scilit:
- Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastomaNeuro-Oncology, 2011
- Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4+ T cells from patients with GI malignancyCancer Immunology, Immunotherapy, 2011
- Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and functionTrends in Immunology, 2010
- Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trialsThe Lancet, 2010
- Dendritic CellsThe Cancer Journal, 2010
- Immunosuppressive CD14+HLA‐DRlow/− monocytes in prostate cancerThe Prostate, 2009
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- A New Population of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients Induces CD4+CD25+Foxp3+ T CellsGastroenterology, 2008
- Regulation of immune responses by L-arginine metabolismNature Reviews Immunology, 2005
- Mechanisms and functional significance of tumour-induced dendritic-cell defectsNature Reviews Immunology, 2004