PGE2 induced in and released by dying cells functions as an inhibitory DAMP
PGE2 induced in and released by dying cells functions as an inhibitory DAMP
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DOI：
10.1073/pnas.1602023113
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发表时间：
2016-04-05
影响因子：
11.1
通讯作者：
Yanai, Hideyuki
中科院分区：
文献类型：
--
作者：
Hangai, Sho;Ao, Tomoka;Yanai, Hideyuki
由于细胞死亡而释放到外部环境中并被身体感知的细胞成分通常称为损伤相关分子模式（DAMP）。尽管DAMP通常被认为通过引起对免疫和伤口修复重要的炎症反应而对宿主具有保护性，但普遍的观点是DAMP的失调释放也可能成为疾病发展的基础或加剧疾病发展。然而，迄今为止尚未完全解决如何调节所得DAMP介导的应答的关键问题。在本研究中，我们确定前列腺素E2（PGE2）作为DAMP，负调节免疫反应。我们表明，PGE2的生产增加细胞死亡诱导条件下，通过转录诱导的环氧合酶2（COX2）基因和细胞释放的PGE2抑制与炎症相关的基因的表达，从而限制了细胞的免疫刺激活性。与此一致，PGE2合成途径的抑制增强了由垂死细胞诱导的炎症。我们还提供了体内证据，对乙酰氨基酚诱导的肝损伤后释放的PGE2的保护作用，以及PGE2在肿瘤细胞生长过程中的致病作用。我们的研究将这种经典已知的脂质介质置于前所未有的背景下，即抑制性DAMP维斯激活DAMP相比，这可能对设计更有效的炎症相关疾病治疗方案具有翻译意义。
Cellular components released into the external milieu as a result of cell death and sensed by the body are generally termed damage-associated molecular patterns (DAMPs). Although DAMPs are conventionally thought to be protective to the host by evoking inflammatory responses important for immunity and wound repair, there is the prevailing notion that dysregulated release of DAMPs can also underlie or exacerbate disease development. However, the critical issue for how resultant DAMP-mediated responses are regulated has heretofore not been fully addressed. In the present study, we identify prostaglandin E2 (PGE2) as a DAMP that negatively regulates immune responses. We show that the production of PGE2 is augmented under cell death-inducing conditions via the transcriptional induction of the cyclooxygenase 2 (COX2) gene and that cell-released PGE2 suppresses the expression of genes associated with inflammation, thereby limiting the cell's immunostimulatory activities. Consistent with this, inhibition of the PGE2 synthesis pathway potentiates the inflammation induced by dying cells. We also provide in vivo evidence for a protective role of PGE2 released upon acetaminophen-induced liver injury as well as a pathogenic role for PGE2 during tumor cell growth. Our study places this classically known lipid mediator in an unprecedented context-that is, an inhibitory DAMP vis-a-vis activating DAMPs, which may have translational implications for designing more effective therapeutic regimens for inflammation-associated diseases.