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

我们本研究的主要目的是通过建立大鼠角叉菜胶外周炎症模型，探讨炎症性痛觉过敏过程中前列腺素相关的中枢致敏机制。结果表明，合成前列腺素E_2 （PG E_2）所必需的酶；环氧化酶2 （COX-2）和膜型PGE合成酶（mPGES）在整个中枢神经系统血管内皮细胞中表达，无区域差异。在大多数血管内皮细胞中，这些酶在细胞核中共定位。通过原位杂交也检测到这些细胞的MPGES mRNA。COX-2与血管内皮细胞中mPGES表达、PGE_2合成及释放到脑脊液中与行为性痛觉过敏有很好的相关性。鞘内注射选择性COX-2抑制剂可减轻晚期痛觉过敏。这些血管内皮细胞可能在外周炎症诱导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确定参与炎症信号从外周炎症部位传递到中枢神经系统的分子。首先，我们在同一模型中测量了血清中各种促炎细胞因子的水平。卡拉胶注射后3小时血浆中白细胞介素6 （IL-6）显著升高，但IL-1和肿瘤坏死因子无显著升高。IL-6中和酶预处理大鼠可抑制中枢神经血管内皮细胞COX-2和mPGES的表达，抑制PGE_2的体外释放，部分缓解行为性痛觉过敏。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.