Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells
Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells
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DOI：
10.1182/blood-2011-07-365825
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发表时间：
2011-11-17
期刊：
影响因子：
20.3
通讯作者：
Kalinski, Pawel
中科院分区：
文献类型：
--
作者：
Obermajer, Natasa;Muthuswamy, Ravikumar;Kalinski, Pawel
树突状细胞（DC）和髓源性抑制细胞（MDSC）在免疫系统中表现出相反的作用。在本研究中，我们报告了前列腺素E-2（PGE（2））和环氧合酶2（COX 2）（PGE（2）合成的关键调节因子）之间的正反馈环的建立，代表了将CD1a（+）DCs重定向为CD14（+）CD33（+）CD34（+）单核MDSC的决定因素。外源性PGE（2）和不同的COX2激活剂如脂多糖、IL-1 β和IFN γ均诱导单核细胞表达COX2，阻断其分化为CD1a（+）DC，并诱导内源性PGE（2）、IDO 1、IL-4R α、NOS 2和IL-10，典型的MDSC相关抑制因子。在添加GM-CSF/IL-4的单核细胞培养物中加入PGE（2）足以诱导MDSC表型和细胞毒性T淋巴细胞（CTL）抑制功能。根据PGE（2）在人MDSC生理诱导中的关键作用，卵巢癌中CD11b（+）CD33（+）MDSC的频率与局部PGE（2）的产生密切相关，而癌症促进的MDSC诱导是严格依赖于COX 2的。使用COX2抑制剂或EP2和EP4拮抗剂破坏COX2-PGE（2）反馈抑制了MDSC相关抑制因子的产生和来自癌症患者的完全发育的MDSC的CTL抑制功能。COX2-PGE（2）反馈在MDSC诱导和持续中的核心作用突出了其操纵以增强或抑制癌症、自身免疫或移植中的免疫应答的潜力。（血。2011; 118（20）：5498 - 5505）
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 E-2 (PGE(2)) and cyclooxygenase 2 (COX2), the key regulator of PGE(2) 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 lipopolysaccharide, IL-1 beta, and IFN gamma all induce monocyte expression of COX2, blocking their differentiation into CD1a(+) DCs and inducing endogenous PGE(2), IDO1, IL-4R alpha, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE(2) to GM-CSF/IL-4-supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)-uppressive 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 are closely correlated with local PGE(2) production, whereas the 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. (Blood. 2011;118(20):5498-5505)