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Effects of prostaglandin E2 on the production of chemokines by dendritic cells.

机译：前列腺素E2对树突状细胞产生趋化因子的影响。

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摘要

Dendritic cells bridge innate and adaptive immunity, and are active participants in both responses. Upon capture of pathogens, dendritic cells release inflammatory cytokines and chemokines, which attract other immune cells to the site of infection. Endogenous agents such as anti-inflammatory cytokines, glucocorticoids, anti-inflammatory neuropeptides, and lipid mediators such as prostaglandin E2 (PGE2) limit and control the inflammatory response. PGE2 was reported to inhibit inflammatory chemokine release from activated macrophages and microglia. In this study we report on the inhibition by PGE2 of CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) expression and release from murine bone marrow-derived dendritic cells stimulated with either lipopolysaccharide (LPS), a TLR4 ligand, or peptidoglycan, a TLR2 ligand. The inhibition is dose-dependent, and occurs at both mRNA and protein levels. Intraperitoneal administration of PGE2 together with LPS results in a reduction in the levels of CCL3 and CCL4 released in the peritoneal fluid, a reduction in the number of dendritic cells accumulating in the peritoneal cavity, and a reduction in CCL3 amount per cell in the peritoneal dendritic cell population. These results suggest that one of the mechanisms by which endogenous PGE2 acts as an anti-inflammatory agent, is the inhibition of inflammatory chemokine release from activated dendritic cells, preventing the excess accumulation of activated immune cells.; The inhibitory effect of PGE2 on CCL3/4 expression is mediated through EP2 and EP4 receptors. Bone marrow-derived dendritic cells express both EP-2 and EP-4 receptors and increase intracellular cAMP formation following PGE2 challenge. Intracellular cAMP activates the Epac → PI3K → PKB → GSK-3 pathway, resulting in phosphorylation and thereby inactivation of GSK-3. Active GSK-3 is required for the phosphorylation of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor. Phosphorylated CDP cannot bind DNA and loses the repressor activity. The inactivation of GSK-3 by PGE2 leads to the accumulation of nonphosphorylated CDP, and subsequent CDP binding to specific DNA regions in the CCL3/4 promoters and repression of CCL3/4 transcription. The direct link between CDP and CCL3/4 transcription was established in experiments in which CDP expression was knocked-down by using CDP siRNA which led to the reversal of the inhibitory effects of PGE2.
机译：树突状细胞桥接先天免疫和适应性免疫，并且是两种反应的积极参与者。捕获病原体后，树突状细胞释放出炎性细胞因子和趋化因子，从而将其他免疫细胞吸引到感染部位。内源性药物（例如抗炎细胞因子，糖皮质激素，抗炎性神经肽）和脂质介体（例如前列腺素E2（PGE2））限制并控制了炎症反应。据报道，PGE 2抑制炎性趋化因子从活化的巨噬细胞和小胶质细胞释放。在这项研究中，我们报道了PGE2对CCL3（MIP-1alpha）和CCL4（MIP-1beta）表达的抑制作用，以及从脂多糖（LPS），TLR4配体或肽聚糖刺激的小鼠骨髓来源的树突状细胞释放的抑制作用， TLR2配体。该抑制是剂量依赖性的，并且在mRNA和蛋白质水平上均发生。腹膜内施用PGE2与LPS导致腹膜液中释放的CCL3和CCL4含量降低，腹膜腔中积累的树突状细胞数量减少以及腹膜树突状细胞中每个细胞的CCL3量减少细胞数量。这些结果表明，内源性PGE 2充当抗炎剂的机制之一是抑制活化的树突状细胞释放炎性趋化因子，从而防止活化的免疫细胞过度积聚。 PGE2对CCL3 / 4表达的抑制作用是通过EP2和EP4受体介导的。骨髓来源的树突状细胞同时表达EP-2和EP-4受体，并在PGE2攻击后增加细胞内cAMP的形成。细胞内cAMP激活Epac→PI3K→PKB→GSK-3途径，导致磷酸化，从而使GSK-3失活。活性GSK-3是CCAAT置换蛋白（CDP）（一种有效的哺乳动物转录阻遏物）的磷酸化所必需的。磷酸化的CDP无法结合DNA，并失去阻遏物活性。 PGE2使GSK-3失活会导致非磷酸化CDP的积累，以及随后CDP与CCL3 / 4启动子中特定DNA区域的结合以及CCL3 / 4转录的抑制。在实验中建立了CDP和CCL3 / 4转录之间的直接联系，在该实验中，使用CDP siRNA敲低了CDP的表达，从而逆转了PGE2的抑制作用。

著录项

  • 作者

    Jing, Huie.;

  • 作者单位

    Rutgers The State University of New Jersey - Newark.;

  • 授予单位 Rutgers The State University of New Jersey - Newark.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 126 p.
  • 总页数 126
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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