Estrogen Prevents the Lipopolysaccharide-Induced Inflammatory Response in Microglia
Estrogen Prevents the Lipopolysaccharide-Induced Inflammatory Response in Microglia
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DOI：
10.1523/jneurosci.21-06-01809.2001
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发表时间：
2001-03
期刊：
影响因子：
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通讯作者：
E. Vegeto;C. Bonincontro;G. Pollio;A. Sala;S. Viappiani;F. Nardi;A. Brusadelli;B. Viviani;P. Ciana;A. Maggi
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文献类型：
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作者：
E. Vegeto;C. Bonincontro;G. Pollio;A. Sala;S. Viappiani;F. Nardi;A. Brusadelli;B. Viviani;P. Ciana;A. Maggi
在神经元损伤后以及在一些神经退行性疾病中，激活的小胶质细胞分泌促炎分子，这些分子可以促进进行性神经损伤。最近在人类和实验动物模型中证明雌激素在神经退行性疾病中具有保护作用，这促使我们研究这种激素是否调节中枢神经系统的炎症反应。我们在这里显示雌激素对原代培养的大鼠小胶质细胞具有抗炎活性，这是通过阻断与激活相关的表型转换以及通过阻止内毒素诱导的炎症介质：诱导型一氧化氮合酶(INOS)、前列腺素E_2(PGE_2)和金属蛋白酶-9(MMP-9)的产生而提示的。这些作用是剂量依赖的，在1 nm 17β-雌二醇时最大，并可被雌激素受体(ER)拮抗剂ICI182,780阻断。ERα和ERβ在小胶质细胞和巨噬细胞中的表达，以及雌激素对MMP9mRNA积聚和MMP9启动子诱导的阻断，进一步支持了雌激素通过细胞内受体发挥基因组活性的假说。这是第一个显示雌激素在小胶质细胞中具有抗炎活性的报告。我们的研究为雌激素在神经退行性疾病和炎症性疾病中的保护作用提出了新的解释，并为筛选作用于中枢神经系统的ER配体提供了新的分子和细胞靶点。
After neuronal injury and in several neurodegenerative diseases, activated microglia secrete proinflammatory molecules that can contribute to the progressive neural damage. The recent demonstration of a protective role of estrogen in neurodegenerative disorders in humans and experimental animal models led us to investigate whether this hormone regulates the inflammatory response in the CNS. We here show that estrogen exerts an anti-inflammatory activity on primary cultures of rat microglia, as suggested by the blockage of the phenotypic conversion associated with activation and by the prevention of lipopolysaccharide-induced production of inflammatory mediators: inducible form of NO synthase (iNOS), prostaglandin-E2 (PGE2), and metalloproteinase-9 (MMP-9). These effects are dose-dependent, maximal at 1 nm 17β-estradiol, and can be blocked by the estrogen receptor (ER) antagonist ICI 182,780. The demonstration of ERα and ERβ expression in microglia and macrophages and the observation of estrogen blockade of MMP-9 mRNA accumulation and MMP-9 promoter induction further support the hypothesis of a genomic activity of estrogen via intracellular receptors. This is the first report showing an anti-inflammatory activity of estrogen in microglia. Our study proposes a novel explanation for the protective effects of estrogen in neurodegenerative and inflammatory diseases and provides new molecular and cellular targets for the screening of ER ligands acting in the CNS.