Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells
Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells
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DOI：
10.1210/en.2012-1375
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发表时间：
2012-10-01
期刊：
影响因子：
4.8
通讯作者：
Blomqvist, Anders
中科院分区：
文献类型：
--
作者：
Engstrom, Linda;Ruud, Johan;Blomqvist, Anders
免疫诱导的前列腺素E2 （PGE2）合成对发烧和其他中枢引起的疾病症状至关重要。PGE2的产生依赖于环氧化酶-2和微粒体前列腺素E合成酶-1 (mPGES-1)，但参与的细胞的身份一直是一个有争议的问题。我们在造血细胞或非造血细胞中培养了表达mPGES-1的小鼠。造血细胞中缺乏pge1的小鼠对脂多糖表现出完整的发热反应，这与脑脊液中PGE2水平升高有关。相比之下，仅在造血细胞中表达mPGES-1的小鼠，尽管血浆中PGE2水平升高，但脑脊液中PGE2水平未升高，但对脂多糖没有发热反应，这表明脑源性PGE2在发热中起关键作用。免疫组织化学染色显示，诱导的环氧化酶-2在脑内的表达只发生在内皮细胞中，流式细胞术分离的脑细胞的定量PCR分析表明，mPGES-1在内皮细胞中被诱导，而不是在血管壁巨噬细胞中被诱导。对肝细胞的类似分析显示，巨噬细胞而非内皮细胞诱导了PGE2的表达，这表明脑内皮细胞在PGE2合成中的独特作用。这些结果确定脑内皮细胞是产生pge2的细胞，对免疫诱导的发烧至关重要。（内分泌学153:4849-4861,2012）
Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever. (Endocrinology 153: 4849-4861, 2012)