| Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells towards stable myeloid-derived suppressor cells. | |
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MedLine Citation:
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PMID: 21972293 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. We report that the establishment of positive feedback loop between prostaglandin E(2) (PGE(2)) and 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 PGE(2) and such diverse COX2 activators as LPS, IL-1β or IFNγ, all induce monocyte expression of COX2, blocking their differentiation into CD1a(+) DCs and induce endogenous PGE(2), IDO1, IL4Rα, NOS2 and IL-10, typical MDSC-associated suppressive factors. Addition of PGE(2) to GM-CSF/IL-4-supplemented monocyte cultures is sufficient to induce MDSC phenotype and CTL-suppressive function. In accordance with the key role of PGE(2) in the physiologic induction of human MDSCs, the frequencies of CD11b(+)CD33(+) MDSCs in ovarian cancer closely correlate with local PGE(2) production, while cancer-promoted induction of MDSCs is strictly COX2-dependent. The disruption of COX2-PGE(2) 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-PGE(2) 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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Authors:
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Natasa Obermajer; Ravikumar Muthuswamy; Jamie Lesnock; Robert P Edwards; Pawel Kalinski |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-4 |
Journal Detail:
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Title: Blood Volume: - ISSN: 1528-0020 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-5 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Surgery, University of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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