PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4)
PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4)
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DOI：
10.1016/j.molimm.2012.12.010
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发表时间：
2013-07-01
影响因子：
3.6
通讯作者：
Woodward, David F.
中科院分区：
文献类型：
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作者：
Poloso, Neil J.;Urquhart, Paula;Woodward, David F.
树突状细胞（DC）是协调先天性和适应性免疫反应的核心参与者。虽然脂质介质在免疫应答中的作用一直是许多研究的主题，但野牡丹素的确切作用经常受到相互矛盾的研究的困扰。在这项研究中，我们研究了PGE（2）对人DC功能的作用。尽管研究表明PGE（2）在DC运动和细胞因子释放中起特定作用，但确切的受体使用和涉及的信号通路仍不清楚。在这份报告中，我们发现，无论人类供体，单核细胞来源的树突状细胞（MoDC）表达四种PGE（2）受体亚型（EP 2 -4）中的三种，尽管只有EP 2和EP 4在细胞因子产生方面具有活性。使用选择性EP受体拮抗剂和激动剂，我们证明PGE（2）通过在LPS激活的MoDC中不同使用EP 2和EP 4受体，以剂量依赖性方式协调IL-23释放（Th 17的启动子，一种自身免疫相关T细胞亚群）的控制。这与IL-12相反，IL-12通过两种受体亚型被PGE（2）剂量依赖性地抑制。低浓度（类似于1-10 nM）的PGE（2）通过EP 4受体促进IL-23的产生，而在较高（>50 nM）但仍具有生理相关性的浓度下，IL-23被EP 2依赖性机制抑制。这些结果可以通过EP 2和EP 4对共同亚基IL-12 p40和IL-23 p19的差异调节来解释。通过这些方法，PGE（2）可以根据其在微环境中的浓度作为免疫反应的调节开关。此外，我们认为这些结果也可以解释为什么文献中报告了PGE（2）的看似相互矛盾的生物学功能，因为配体（PGE（2））的浓度从根本上改变了反应的性质。这一发现也突出了设计差异靶向这些受体的治疗方法的潜力。(C)2013爱思唯尔有限公司保留所有权利。
Dendritic cells (DCs) are central players in coordinating immune responses, both innate and adaptive. While the role of lipid mediators in the immune response has been the subject of many investigations, the precise role of prostaglandins has often been plagued by contradictory studies. In this study, we examined the role of PGE(2) on human DC function. Although studies have suggested that PGE(2) specifically plays a role in DC motility and cytokine release profile, the precise receptor usage and signaling pathways involved remain unclear. In this report we found that irrespective of the human donor, monocyte-derived dendritic cells (MoDCs) express three of the four PGE(2) receptor subtypes (EP2-4), although only EP2 and EP4 were active with respect to cytokine production. Using selective EP receptor antagonists and agonists, we demonstrate that PGE(2) coordinates control of IL-23 release (a promoter of Th17, an autoimmune associated T cell subset) in a dose-dependent manner by differential use of EP2 and EP4 receptors in LPS-activated MoDCs. This is in contrast to IL-12, which is dose dependently inhibited by PGE(2) through both receptor subtypes. Low concentrations (similar to 1-10 nM) of PGE(2) promoted IL-23 production via EP4 receptors, while at higher (>50 nM), but still physiologically relevant concentrations, IL-23 is suppressed by an EP2 dependent mechanism. These results can be explained by differential regulation of the common subunit, IL-12p40, and IL-23p19, by EP2 and EP4. By these means, PGE(2) can act as a regulatory switch of immune responses depending on its concentration in the microenvironment. In addition, we believe these results may also explain why seemingly conflicting biological functions assigned to PGE(2) have been reported in the literature, as the concentration of ligand (PGE(2)) fundamentally alters the nature of the response. This finding also highlights the potential of designing therapeutics which differentially target these receptors. (C) 2013 Elsevier Ltd. All rights reserved.