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  • Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells towards stable myeloid-derived suppressor cells
    Obermajer, Nataša ...
    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 E2 (PGE2) ... 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 PGE2 and such diverse COX2 activators as LPS, IL-1? or IFN?, all induce monocyte expression of COX2, blocking their differentiation into CD1a+ DCs andinduce endogenous PGE2, IDO1, IL4R?, NOS2 and IL-10, typical MDSC-associated suppressive factors. Addition of PGE2 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 PGE2 in the physiologic induction of human MDSCs, the frequencies of CD11b+CD33+ MDSCs in ovarian cancer closely correlate with local PGE2 production, while 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.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 E2 (PGE2) 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 PGE2 and such diverse COX2 activators as LPS, IL-1? or IFN?, all induce monocyte expression of COX2, blocking their differentiation into CD1a+ DCs and induce endogenous PGE2, IDO1, IL4R?, NOS2 and IL-10, typical MDSC-associated suppressive factors. Addition of PGE2 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 PGE2 in the physiologic induction of human MDSCs, the frequencies of CD11b+CD33+ MDSCs in ovarian cancer closely correlate with local PGE2 production, while 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.
    Source: Blood. - ISSN 0006-4971 (Vol. 118, no. 20, 2011, str. 5498-5505)
    Type of material - article, component part
    Publish date - 2011
    Language - english
    COBISS.SI-ID - 3111793

    Link(s):

    http://bloodjournal.hematologylibrary.org/search?fulltext=Positive+feedback&volume=&issue=&submit=yes&x=0&y=0
    http://bloodjournal.hematologylibrary.org/content/early/2011/10/04/blood-2011-07-365825.abstract?sid=9b687a38-4208-4f64-92b2-26dd876100ce
    DOI

source: Blood. - ISSN 0006-4971 (Vol. 118, no. 20, 2011, str. 5498-5505)
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