Production of Proinflammatory Cytokines and Chemokines During Neuroinflammation: Novel Roles for Estrogen Receptors α and β
Production of Proinflammatory Cytokines and Chemokines During Neuroinflammation: Novel Roles for Estrogen Receptors α and β
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DOI：
10.1210/en.2010-0371
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Wise, Phyllis M.
中科院分区：
文献类型：
--
作者：
Brown, Candice M.;Mulcahey, Tara A.;Wise, Phyllis M.
神经炎症是许多神经系统疾病的共同特征，并且它通常伴随着促炎细胞因子和趋化因子的释放。在中枢神经系统中，E3 -17 β（E（2））表现出抗炎特性，包括抑制促炎细胞因子。然而，E（2）的作用机制和雌激素受体（ER）ER α和ER β的作用尚不清楚。为了研究这些机制，我们在卵巢切除（OVX）和OVX + E（2）治疗（OVX + E（2））小鼠中采用了体内脂多糖（LPS）全身炎症模型。在感染后0（假手术）、3、6、12和24 h，使用多重蛋白质分析定量小鼠中促炎细胞因子（IL-1 β、IL-6和IL-12 p40）和趋化因子（CCL 2/MCP-1、CCL 3/MIP-1 α、CCL 5/RANTES和CXCL 1/KC）的脑水平。E（2）处理抑制LPS诱导的所有细胞因子的增加。相反，E（2）处理仅抑制CCL/RANTES趋化因子浓度。为了确定ER α和ER β是否调节脑细胞因子和趋化因子水平，使用ER α敲除和ER β敲除小鼠进行平行实验。我们的研究结果表明，ER α和ER β都通过E（2）依赖和E（2）非依赖机制调节促炎细胞因子和趋化因子的产生。为了评估血脑屏障的破坏是否是E（2）对抗LPS诱导的神经炎症的另一个靶点，我们测量了Evan's blue外渗，并确定了ER α和ER β的不同作用。总之，这些研究确定了一个戏剧性的细胞因子和趋化因子介导的神经炎症反应，通过ER α和ER β介导的配体依赖性和配体非依赖性机制进行调节。（内分泌学151：4916-4925，2010）
Neuroinflammation is a common feature of many neurological disorders, and it is often accompanied by the release of proinflammatory cytokines and chemokines. Estradiol-17 beta (E(2)) exhibits antiinflammatory properties, including the suppression of proinflammatory cytokines, in the central nervous system. However, the mechanisms employed by E(2) and the role(s) of estrogen receptors (ERs) ER alpha and ER beta are unclear. To investigate these mechanisms, we employed an in vivo lipopolysaccharide (LPS) model of systemic inflammation in ovariectomized (OVX) and OVX and E(2)-treated (OVX + E(2)) mice. Brain levels of proinflammatory cytokines (IL-1 beta, IL-6, and IL-12p40) and chemokines (CCL2/MCP-1, CCL3/MIP-1 alpha, CCL5/RANTES, and CXCL1/KC) were quantified in mice at 0 (sham), 3, 6, 12, and 24 h after infection using multiplex protein analysis. E(2) treatment inhibited LPS-induced increases in all cytokines. In contrast, E(2) treatment only suppressed CCL/RANTES chemokine concentrations. To determine whether ER alpha and ER beta regulate brain cytokine and chemokine levels, parallel experiments were conducted using ER alpha knockout and ER beta knockout mice. Our results revealed that both ER alpha and ER beta regulated proinflammatory cytokine and chemokine production through E(2)-dependent and E(2)-independent mechanisms. To assess whether breakdown of the blood-brain barrier is an additional target of E(2) against LPS-induced neuroinflammation, we measured Evan's blue extravasation and identified distinct roles for ER alpha and ER beta. Taken together, these studies identify a dramatic cytokine- and chemokine-mediated neuroinflammatory response that is regulated through ER alpha- and ER beta-mediated ligand-dependent and ligand-independent mechanisms. (Endocrinology 151: 4916-4925, 2010)