Department of Biochemistry and Molecular Biology, University of Valladolid, Valladolid, Spain (M.R., N.F.); and Institute of Biology and Molecular Genetics, Spanish National Research Council, Valladolid, Spain (E.D., C.M., Y.A., E.H., M.S.C.).
Mol Pharmacol. 2014 Jan;85(1):187-97. doi: 10.1124/mol.113.089573. Epub 2013 Oct 29.
Eicosanoids tailor the innate immune response by supporting local inflammation and exhibiting immunomodulatory properties. Prostaglandin (PG) E2 is the most abundant eicosanoid in the inflammatory milieu due to the robust production elicited by pathogen-associated molecular patterns on cells of the innate immune system. The different functions and cell distribution of E prostanoid receptors explain the difficulty encountered thus far to delineate the actual role of PGE2 in the immune response. The biosynthesis of eicosanoids includes as the first step the Ca(2+)- and kinase-dependent activation of the cytosolic phospholipase A2, which releases arachidonic acid from membrane phospholipids, and later events depending on the transcriptional regulation of the enzymes of the cyclooxygenase routes, where PGE2 is the most relevant product. Acting in an autocrine/paracrine manner in macrophages, PGE2 induces a regulatory phenotype including the expression of interleukin (IL)-10, sphingosine kinase 1, and the tumor necrosis factor family molecule LIGHT. PGE2 also stabilizes the suppressive function of myeloid-derived suppressor cells, inhibits the release of IL-12 p70 by macrophages and dendritic cells, and may enhance the production of IL-23. PGE2 is a central component of the inflammasome-dependent induction of the eicosanoid storm that leads to massive loss of intravascular fluid, increases the mortality rate associated with coinfection by Candida ssp. and bacteria, and inhibits fungal phagocytosis. These effects have important consequences for the outcome of infections and the polarization of the immune response into the T helper cell types 2 and 17 and can be a clue to develop pharmacological tools to address infectious, autoimmune, and autoinflammatory diseases.
类二十烷酸通过支持局部炎症和表现出免疫调节特性来调整先天免疫反应。由于先天免疫系统细胞对病原体相关分子模式的强烈反应，前列腺素 (PG) E2 是炎症环境中最丰富的类二十烷酸。E 前列腺素受体的不同功能和细胞分布解释了迄今为止在阐明 PGE2 在免疫反应中的实际作用时所遇到的困难。类二十烷酸的生物合成包括作为第一步的细胞质磷脂酶 A2 的 Ca2+和激酶依赖性激活，该酶从膜磷脂中释放花生四烯酸，以及随后取决于环氧化酶途径的酶的转录调节的事件，其中 PGE2 是最相关的产物。在巨噬细胞中以自分泌/旁分泌方式起作用的 PGE2 诱导调节表型，包括白细胞介素 (IL)-10、鞘氨醇激酶 1 和肿瘤坏死因子家族分子 LIGHT 的表达。PGE2 还稳定髓源性抑制细胞的抑制功能，抑制巨噬细胞和树突状细胞中 IL-12 p70 的释放，并可能增强 IL-23 的产生。PGE2 是导致大量血管内液体流失的炎症小体依赖性诱导类二十烷酸风暴的核心成分，增加了与念珠菌属和细菌共感染相关的死亡率，并抑制真菌吞噬作用。这些影响对感染的结果和免疫反应向辅助性 T 细胞类型 2 和 17 的极化具有重要意义，并可能为开发解决感染性、自身免疫性和自身炎症性疾病的药理学工具提供线索。
