The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells
Open accessAbstract
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.
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Cites
Myeloid-derived-suppressor cells as regulators of the immune system
Gabrilovich, D. I., & Nagaraj, S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2506 · Cited by 6,753
Ido expression by dendritic cells: tolerance and tryptophan catabolism
Mellor, A. L., & Munn, D. H. (2004) · Nature Reviews Immunology · doi:10.1038/nri1457 · Cited by 2,341
Regulation of immune responses by L-arginine metabolism
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Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity
Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., Krzysiek, R., Knutson, K. L., Daniel, B., Zimmermann, M. C., et al. (2003) · Nature Medicine · doi:10.1038/nm863 · Cited by 1,314
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Cited by
Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.09.003 · Cited by 609
“…because the former has consistently been implicated in the induction of immunosuppressive myeloid cells in cancer patients (Mao et al., 2013, 2014; Obermajer et al., 2011) and the latter has been shown to trigger myeloid cell-mediated NK cell inhibition (Li et al., 2009; Mao et al., 2014).”
Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets
Tie, Y., Tang, F., Wei, Y.-Q., & Wei, X.-W. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01282-8 · Cited by 591
Erin, N., Grahovac, J., Brozovic, A., & Efferth, T. (2020) · Drug Resistance Updates · doi:10.1016/j.drup.2020.100715 · Cited by 527
Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance
Khalaf, K., Hana, D., Chou, J. T.-T., Singh, C., Mackiewicz, A., & Kaczmarek, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.656364 · Cited by 513
Ostrand-Rosenberg, S., & Fenselau, C. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701019 · Cited by 509
Metadata
- Authors
- Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R. P., & Kalinski, P.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-11-17
- Volume
- 118
- Issue
- 20
- Pages
- 5498-5505
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2039146285
- Cited by
- 497
- References
- 9
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- green
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- Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R. P., & Kalinski, P. (2011). Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. https://doi.org/10.1182/blood-2011-07-365825
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