Ching San, Zhang Hao, Belevych Natalya, He Lingli, Lai Wenmin, Pu Xin-an, Jaeger Laura B, Chen Qun, Quan Ning
Department of Oral Biology, Ohio State University, Columbus, Ohio 43210-1094, USA
J Neurosci. 2007 Sep 26;27(39):10476-86. doi: 10.1523/JNEUROSCI.3357-07.2007.
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.
白细胞介素-1（IL-1）被认为是神经免疫通讯的关键介质。在大脑中，IL-1的功能性受体，即1型IL-1受体（IL-1R1），主要定位于内皮细胞。在本研究中，我们创建了一种内皮细胞特异性IL-1R1敲低模型，以测试内皮细胞IL-1R1在介导IL-1作用中的作用。通过室旁核和腹内侧视前区的c-fos表达来测量下丘脑的神经元激活。此外，还研究了两种特定的疾病症状，即发热反应和运动活动减少。向正常小鼠脑室内注射IL-1可诱导白细胞浸润到中枢神经系统、下丘脑神经元激活、发热和运动活动减少。内皮细胞特异性敲低IL-1R1可消除所有这些反应。腹腔注射IL-1也可诱导下丘脑神经元激活、发热和运动活动减少，但不会诱导白细胞浸润到大脑中。内皮细胞特异性敲低IL-1R1可抑制腹腔注射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，内皮细胞敲低IL-1R1可消除静脉注射IL-1诱导的中枢神经系统激活和两种监测到的疾病症状。此外，内皮细胞特异性敲低IL-1R1可阻断由所有三种IL-1给药途径诱导的环氧化酶-2表达。这些结果表明，静脉注射和脑室内注射IL-1的作用是由内皮细胞IL-1R1介导的，而腹腔注射IL-1的作用部分依赖于内皮细胞IL-1R1。
