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Discovery of novel functions of brain microglia and their in vivo analysis.

Discovery of novel functions of brain microglia and their in vivo analysis.
脑小胶质细胞新功能的发现及其体内分析。
批准号:
11670089
负责人:
NAKATA Yoshihiro
金额:
$1.92万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (C)
财政年份:
1999
资助国家:
日本
项目状态:
已结题
起止时间:
1999 至 2000

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中文摘要
翻译
在脑缺血或炎症等病理改变时,小胶质细胞被迅速激活并分泌各种细胞因子,包括TNF-α,对神经元既有伤害作用,也有保护作用。尽管小胶质细胞衍生的TNF-α很重要,但TNF-α的释放是如何调节的仍然未知。近年来研究发现,神经末梢释放的ATP可激活免疫细胞或受损细胞,并通过细胞表面P2受体(至少是g蛋白偶联的P2Y_2和嗜离子性的P2X_7)激活小胶质细胞。在本研究中,我们发现ATP刺激TNF-α的释放,导致mRNA在大鼠培养的脑小胶质细胞中表达。大鼠P2X_7受体选择性拮抗剂Brilliant Blue G可抑制2′和3′- o -(4-苯甲酰苯甲酰)-腺苷5′-三磷酸(BzATP)诱导的TNF-α释放。活化ERK的MEK1抑制剂PD98059和U-0126以及p38 MAP激酶抑制剂SB203580均能抑制atp或bzatp诱导的TNF-α释放,而bzatp刺激的TNF-α mRNA表达被U-0126抑制,而SB203580则不能。这些结果表明,细胞外ATP至少通过P2X_7受体触发大鼠小胶质细胞中TNF-α的释放,并提示TNF-α释放的信号通路涉及ERK和p38 MAP激酶,它们分别在转录和转录后水平上发挥不同的作用。
英文摘要
Upon pathological changes such as brain ischemia or inflammation, microglia are rapidly activated and secrete various cytokines, including TNF-α, which plays not only harmful, but also protective roles for neurons. Despite importance of microglia-derived TNF-α, it remains unknown how the release of TNF-α is regulated. Recently it was revealed that ATP, which is released from nerve terminals, activated immune cells or damaged cells, activates microglia via cell surface P2 receptors, at least G-protein-coupled P2Y_2 and ionotropic P2X_7. In this study, we found that ATP stimulates the release of TNF-α, resulting from mRNA expression in rat cultured brain microglia. The release of TNF-α was maximally elicited by 1 mM ATP and also induced by a P2X_7 selective agonist, 2'-and 3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP), and BzATP-induced TNF-α was inhibited by Brilliant Blue G, a selective antagonist of rat P2X_7 receptor. ATP-or BzATP-induced TNF-α release was inhibited by PD98059 and U-0126, inhibitors of MEK1, which activates ERK, and also by SB203580, an inhibitor of p38 MAP kinase, while BzATP-stimulated mRNA expression of TNF-α was inhibited by U-0126, but not by SB203580. These results indicate that extracellular ATP triggers TNF-α release in rat microglia at least via P2X_7 receptor and suggest that signaling to the release of TNF-α involves ERK and p38 MAP kinase, which play distinct roles at the transcriptional and the post-transcriptional levels, respectively.
期刊论文(8)
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会议论文
Izumi Hide, Tomohisa Suzuki, Atsuko Inoue, and Yoshihiro Nakata: "Regulation of TNF-α release from microglia by ATP."Neurochemical Research. (in press).
Izumi Hide、Tomohisa Suzuki、Atsuko Inoue 和 Yoshihiro Nakata:“ATP 对小胶质细胞释放 TNF-α 的调节”。神经化学研究(正在出版)。
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通讯作者:
Izumi Hide, Masaya Tanaka, Atsuko Inoue, Kazuyuki Nakajima, Shinichi Kohsaka, Kazuhide Inoue, and Yoshihiro Nakata: "Extracellular ATP triggers tumor necrosis factor-α release from rat microglia."Journal of Neurochemistry. 75. 965-972 (2000)
Izumi Hide、Masaya Tanaka、Atsuko Inoue、Kazuyuki Nakajima、Shinichi Kohsaka、Kazuhide Inoue 和 Yoshihiro Nakata:“细胞外 ATP 触发大鼠小胶质细胞释放肿瘤坏死因子-α。”神经化学杂志 75. 965-972 (2000)。
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通讯作者:
I.Hide,M.Tanaka,A.Inoue,K.Nakajima,S.Kohsaka,K.Inoue & Y.Nakata: "Extracellular ATP triggers tumor necrosis factor-α release from rat microglia."Journal of Neurochemistry. 75. 965-972 (2000)
I.Hide、M.Tanaka、A.Inoue、K.Nakajima、S.Kohsaka、K.Inoue 和 Y.Nakata:“细胞外 ATP 触发大鼠小胶质细胞释放肿瘤坏死因子-α”。《神经化学杂志》75. 965。 -972 (2000)
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通讯作者:
I.Hide,T.Suzuki,A.Inoue,and Y.Nakata: "Regulation of TNF-α release from microglia by ATP"Neurochemical Research. (in press). (2001)
I.Hide、T.Suzuki、A.Inoue 和 Y.Nakata:“ATP 对小胶质细胞释放 TNF-α 的调节”神经化学研究(2001 年出版)。
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通讯作者:
A crosstalk between sensory neurons and surrounding cells
  • 批准号:
    21590280
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 资助金额:
    $3.0万
  • 财政年份:
    2009
  • 负责人:
    NAKATA Yoshihiro
  • 依托单位:
Neuroprotective effects exerted by activated microglia
  • 批准号:
    16390066
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 资助金额:
    $4.93万
  • 财政年份:
    2004
  • 负责人:
    NAKATA Yoshihiro
  • 依托单位:
Development of highly potent vasoactive compounds.
  • 批准号:
    11694281
  • 项目类别:
    Grant-in-Aid for Scientific Research (B).
  • 资助金额:
    $2.75万
  • 财政年份:
    1999
  • 负责人:
    NAKATA Yoshihiro
  • 依托单位:
Pharmacological studies investigating the mechanisms controlling the peptidergic neurotransmitter release.
  • 批准号:
    09670093
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 资助金额:
    $2.05万
  • 财政年份:
    1997
  • 负责人:
    NAKATA Yoshihiro
  • 依托单位:
国内基金
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