Cyclooxygenase-1 mediates prostaglandin E2 elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1β expression
Cyclooxygenase-1 mediates prostaglandin E2 elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1β expression
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DOI：
10.1111/j.1471-4159.2010.06759.x
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发表时间：
2010-07-01
影响因子：
4.7
通讯作者：
O'Banion, M. Kerry
中科院分区：
文献类型：
--
作者：
Matousek, Sarah B.;Hein, Amy M.;O'Banion, M. Kerry
白细胞介素（IL）-1 β是一种与多种神经退行性疾病有关的促炎细胞因子。IL-1 β的下游作用包括通过增加环氧合酶（考克斯）和前列腺素E合酶（PGES）同种型的表达产生前列腺素（PG）E-2。我们最近开发了一种转基因小鼠，其携带休眠的人IL-1 β分泌激活转基因（XAT），用于在选定的脑区域中条件性和慢性上调IL-1 β。该模型的特征在于区域特异性胶质细胞活化、免疫细胞募集以及细胞因子和趋化因子的诱导。在这里，我们的目的是阐明长期IL-1 β表达对PGE（2）合成途径的影响，并确定在我们的模型中前列腺素对炎症和记忆的影响。正如预期的那样，PGE（2）水平在IL-1 β上调后显著升高。定量实时PCR分析表明，考克斯-1和膜PGES-1的mRNA的显著诱导，但考克斯-2或其他PGES亚型没有。免疫组化显示持续IL-1 β产生后考克斯-1升高，但考克斯-2无变化。此外，药理学抑制考克斯-1和使用考克斯-1敲除小鼠消除IL-1 β介导的PGE（2）增加。虽然考克斯-1缺陷小鼠没有表现出显着改变的神经炎性表型，但它们确实表现出改善的背景恐惧记忆。这些数据表明，考克斯-1在通过PGE（2）产生介导慢性神经炎症效应中具有独特的作用。
P>Interleukin (IL)-1 beta is a proinflammatory cytokine implicated in several neurodegenerative disorders. Downstream actions of IL-1 beta include production of prostaglandin (PG) E-2 by increasing expression of cyclooxygenase (COX) enzymes and prostaglandin E synthase (PGES) isoforms. We recently developed a transgenic mouse carrying a dormant human IL-1 beta eXcisional Activation Transgene (XAT) for conditional and chronic up-regulation of IL-1 beta in selected brain regions. This model is characterized by regionally specific glial activation, immune cell recruitment, and induction of cytokines and chemokines. Here, we aimed to elucidate the effects of long-term IL-1 beta expression on the PGE(2) synthetic pathway and to determine the effects of PGs on inflammation and memory in our model. As expected, PGE(2) levels were significantly elevated after IL-1 beta up-regulation. Quantitative real-time PCR analysis indicated significant induction of mRNAs for COX-1 and membranous PGES-1, but not COX-2 or other PGES isoforms. Immunohistochemistry revealed elevation of COX-1 but no change in COX-2 following sustained IL-1 beta production. Furthermore, pharmacological inhibition of COX-1 and use of COX-1 knockout mice abrogated IL-1 beta-mediated PGE(2) increases. Although COX-1 deficient mice did not present a dramatically altered neuroinflammatory phenotype, they did exhibit improved contextual fear memory. This data suggests a unique role for COX-1 in mediating chronic neuroinflammatory effects through PGE(2) production.