Lipopolysaccharide-dependent prostaglandin E2 production is regulated by the glutathione-dependent prostaglandin E2 synthase gene induced by the toll-like receptor 4/MyD88/NF-IL6 pathway
Lipopolysaccharide-dependent prostaglandin E2 production is regulated by the glutathione-dependent prostaglandin E2 synthase gene induced by the toll-like receptor 4/MyD88/NF-IL6 pathway
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DOI：
10.4049/jimmunol.168.11.5811
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发表时间：
2002-06-01
影响因子：
4.4
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Uematsu, S;Matsumoto, M;Akira, S
巨噬细胞在炎症过程中产生大量的PGE 2。这种脂质介质调节各种免疫反应。PGE（2）作用于巨噬细胞并抑制细胞因子如TNF-α和IL-12的产生。膜结合谷胱甘肽依赖性PGE（2）合酶（mPGES）是环加氧酶-2介导的PGE（2）生物合成的末端酶。在这里，我们确定了mPGES作为一种分子，是由LPS诱导的巨噬细胞。在缺乏Toll样受体4或MyD 88的小鼠中，LPS不诱导mPGES的表达。此外，NF-IL 6缺陷的小鼠在对LPS的应答中既没有表现出mPGES的诱导，也没有表现出PGE（2）的生物合成，表明对LPS的应答中mPGES的表达受到Toll样受体4/MyD 88/NF-IL 6依赖性信号通路的调节。我们产生了mPGES缺陷小鼠，并研究了mPGES在体内的作用。小鼠对LPS没有表现出PGE（2）产生的增加。然而，它们在LPS诱导的炎性细胞因子的产生中没有受损，并且对LPS诱导的休克表现出正常反应。因此，mPGES主要参与LPS诱导的PGE（2）的生物合成，但不参与炎症反应的调节。
Macrophages produce a large amount of PGE2 during inflammation. This lipid mediator modulates various immune responses. PGE(2) acts on macrophages and inhibits production of cytokines such as TNF-alpha and IL-12. Membrane-bound glutathione-dependent PGE(2) synthase (mPGES) has been shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE(2) biosynthesis. Here we identified mPGES as a molecule that is induced by LPS in macrophages. The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88. Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES nor biosynthesis of PGE(2) in response to LPS, indicating that mPGES expression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signaling pathway. We generated mPGES-deficient mice and investigated the role of mPGES in vivo. The mice showed no augmentation of the PGE(2) production in response to LPS. However, they were not impaired in the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-induced shock. Thus, mPGES is critically involved in the biosynthesis of PGE(2) induced by LPS, but is dispensable for the modulation of inflammatory responses.