Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration
Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration
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DOI：
10.1523/jneurosci.3357-07.2007
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发表时间：
2007-09-26
影响因子：
5.3
通讯作者：
Quan, Ning
中科院分区：
文献类型：
--
作者：
Ching, San;Zhang, Hao;Quan, Ning
白介素1(IL-1)被认为是神经免疫交流的重要介质。在大脑中，IL-1的功能性受体-1型IL-1受体(IL-1R1)主要定位于内皮细胞。在这项研究中，我们建立了一种内皮特异性IL-1R1基因敲除模型，以测试内皮细胞IL-1R1在介导IL-1效应中的作用。通过c-fos在下丘脑室旁核和视前内侧区的表达来检测下丘脑神经元的激活情况。此外，还研究了两种特殊的疾病症状：发热反应和活动减少。脑室注射IL-1可引起正常小鼠的白细胞渗入中枢神经系统，激活下丘脑神经元，发热，运动能力降低。血管内皮细胞特异性的IL-1R1基因敲除可消除所有这些反应。腹腔注射IL-1还可诱导下丘脑神经元激活、发热和运动能力降低，但不会导致白细胞渗入脑内。内皮特异性的IL-1R1基因敲除可抑制腹膜内IL-1诱导的发热，但不能抑制下丘脑c-fos的诱导。当静脉注射IL-1时，内皮细胞敲除IL-1R1可消除静脉注射IL-1引起的中枢神经系统激活和两种监测到的疾病症状。此外，内皮细胞特异性的IL-1R1基因敲除阻断了所有三种IL-1给药途径诱导的环氧合酶-2的表达。这些结果表明，静脉和脑室内IL-1的作用是由内皮细胞IL-1R1介导的，而腹膜内IL-1的作用部分依赖于内皮细胞IL-1R1。
Interleukin-1 (IL-1) has been implicated as a critical mediator of neuroimmune communication. In the brain, the functional receptor for IL-1, type 1 IL-1 receptor (IL-1R1), is localized primarily to the endothelial cells. In this study, we created an endothelial-specific IL-1R1 knockdown model to test the role of endothelial IL-1R1 in mediating the effects of IL-1. Neuronal activation in the hypothalamus was measured by c-fos expression in the paraventricular nucleus and the ventromedial preoptic area. In addition, two specific sickness symptoms, febrile response and reduction of locomotor activity, were studied. Intracerebroventricular injection of IL-1 induced leukocyte infiltration into the CNS, activation of hypothalamic neurons, fever, and reduced locomotor activity in normal mice. Endothelial-specific knockdown of IL-1R1 abrogated all these responses. Intraperitoneal injection of IL-1 also induced neuronal activation in the hypothalamus, fever, and reduced locomotor activity, without inducing leukocyte infiltration into the brain. Endothelial-specific knockdown of IL-1R1 suppressed intraperitoneal IL-1-induced fever, but not the induction of c-fos in hypothalamus. When IL-1 was given intravenously, endothelial knockdown of IL-1R1 abolished intravenous IL-1-induced CNS activation and the two monitored sickness symptoms. In addition, endothelial-specific knockdown of IL-1R1 blocked the induction of cyclooxygenase-2 expression induced by all three routes of IL-1 administration. These results show that the effects of intravenous and intracerebroventricular IL-1 are mediated by endothelial IL-1R1, whereas the effects of intraperitoneal IL-1 are partially dependent on endothelial IL-1R1.