The involvement of cytokines in the signal transmission mechanism between immune system and central nervous system -Using the inflammatory hyperalgesia model-

本实验采用角叉菜胶诱导的大鼠外周炎性痛敏模型，研究了炎性痛敏过程中与甘草素有关的中枢敏化机制，结果表明：前列腺素E_2（PGE_2）合成所必需的酶;环氧化酶2（考克斯-2）和膜型前列腺素E合成酶（mPGES）在整个中枢神经系统的血管内皮细胞中表达，没有区域差异。在大多数血管内皮细胞中，这些酶共定位于细胞核中。原位杂交检测到MPGES mRNA的表达。考克斯-2和mPGES在血管内皮细胞中的表达、PGE_2合成和释放到脑脊液中的时间过程与行为性痛觉过敏密切相关。鞘内注射选择性考克斯-2抑制剂可减轻晚期痛敏。这些血管内皮细胞可能在外周炎症引起的中枢神经系统激活中起关键作用，本研究的第二个目的是鉴定参与外周炎症部位向中枢神经系统传递炎症信号的分子。首先，我们在同一模型中测定了各种促炎细胞因子的血清水平。注射角叉菜胶后3小时，血浆中白细胞介素6（IL-6）而非IL-1或肿瘤坏死因子显著升高。IL-6中和酶预处理可抑制中枢神经系统血管内皮细胞考克斯-2和mPGES的表达，抑制PGE_2的释放，部分减轻行为性痛觉过敏。这些结果高度提示循环IL-6作为信使分子将炎症信息从外周炎症部位传递到中枢神经系统的可能性。

Our primary purpose of this research was to investigate the mechanism of prostaglandin-related central sensitization during inflammatory hyperalgesia by using the rat model of peripheral inflammation induced by carrageenan.Results have shown that enzymes essential for the synthesis of prostaglandin E_2 (PG E_2) ; cyclooxygenase 2 (COX-2) and membrane-type PGE synthase (mPGES) were expressed in vascular endothelial cells throughout the central nervous system without regional differences. In most of these vascular endothelial cells, these enzymes were co-localized in the nuclei. MPGES mRNA was also detected in these cells by in situ hybridization. The time course of COX-2 and mPGES expression in vascular endothelial cells, PGE_2 synthesis and release to the cerebrospinal fluid and behavioral hyperalgesia correlated very well. Intrathecal injection of selective COX-2 inhibitor alleviated hyperalgesia in the late phase. It was strongly suggested that these vascular endothelial cells may have a key role in the activation of central nervous system induced by peripheral inflammation.The secondary aim of this research was to identify the molecule that is involved in the inflammatory signal transmission from the peripheral inflammatory site to the central nervous system. First, we measured the serum level of various proinflammatory cytokines in the same model. Interleukin 6 (IL-6) but not IL-1 or tumor necrosis factor was significantly elevated in the plasma 3 hrs following carrageenan injection. Pretreatment of rats with IL-6 neutralizing enzyme inhibited the expression of COX-2 and mPGES in vascular endothelial cells in the central nervous system, suppressed the ex vivo release of PGE_2, and partially alleviated behavioral hyperalgesia. These results highly suggest the possibility of circulating IL-6 as a messenger molecule that transmits inflammatory information from the peripheral inflammatory site to the central nervous system.