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

细胞因子参与免疫系统与中枢神经系统信号传递机制-利用炎症性痛觉过敏模型-

• 批准号: 15591656
• 负责人: IBUKI Takae
• 金额: $ 2.24万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591656/
• 关键词: cytokine; inflammatory hyperalgesia; signal transmission; prostaglandin; cyclooxygenase; フォスフォリパーゼA_2; 末梢性炎症; 痛覚過敏

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.

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。

项目成果

Y.Ozaki-Okayama, K.Matsumura, T.Ibuki.et al.: "Burn injury enhances brain prostaglandin E_2 production through induction of cyclooxy genase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats"Criteical Care Medicine. 3

Y.Ozaki-Okayama、K.Matsumura、T.Ibuki.et al.：“烧伤通过诱导大鼠脑血管内皮细胞中环氧化酶-2 和微粒体前列腺素 E 合酶增强脑前列腺素 E_2 的产生”《重症监护医学》。

Transmission mechanism of inflammatory signal to the central nervous system International symposium on spinal cord sciences, Neuroplasticity and stem cell treatment in spinal cord injury

炎症信号向中枢神经系统的传递机制脊髓科学国际研讨会、脊髓损伤的神经可塑性与干细胞治疗

• 发表时间: 2004
• 期刊: 日本臨床麻酔学会会誌 24(1)
• 作者: Ibuki T

Cycooxygenase-2 is induced in the endothelial cells throughout the central nervous system during carrageenan-induced hind paw inflammation ; its possible role in hyperalgesia

在角叉菜胶诱导的后爪炎症期间，整个中枢神经系统的内皮细胞中都会诱导 Cycooxygenase-2；

• 发表时间: 2003
• 期刊: Journal of Neurochemistry 86
• 作者: Ibuki T;Matsumura K;Yamazaki Y;Nozaki T;Tanaka Y;Kobayashi S
• 通讯作者: Kobayashi S

Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats

• DOI: 10.1097/01.ccm.0000114576.60077.fc
• 发表时间: 2004-03
• 期刊: Critical Care Medicine
• 影响因子: 8.8
• 作者: Yoko Ozaki-Okayama;K. Matsumura;T. Ibuki;M. Ueda;Y. Yamazaki;Yoshifumi Tanaka;Shigeo Kobayashi

Spinal amino acid release and repeated withdrawal in spinal morphine tolerant rats

• DOI: 10.1038/sj.bjp.0705102
• 发表时间: 2003-02-01
• 期刊: BRITISH JOURNAL OF PHARMACOLOGY
• 影响因子: 7.3
• 作者: Ibuki, T;Marsala, M;Yaksh, TL
• 通讯作者: Yaksh, TL