| Project/Area Number |
09480216
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Tokyo Metropolitan Institute for Neuroscience |
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Principal Investigator |
MATSUMOTO Yoh Tokyo Metropolitan Inst. for Neurosci., 東京都神経科学総合研究所, 参事研究員 (90173921)
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| Co-Investigator(Kenkyū-buntansha) |
KOHYAMA Kuniko Tokyo Metropolitan Inst. for Neurosci., 東京都神経科学総合研究所, 主事研究員 (80301795)
KAWAZOE Yoko Tokyo Metropolitan Inst. for Neurosci., 東京都神経科学総合研究所, 主事研究員 (60281705)
TANUMA Naoyuki Tokyo Metropolitan Inst. for Neurosci., 東京都神経科学総合研究所, 研究員 (00281676)
小島 崇 (財)東京都神経科学総合研究所, 神経病理研究部門, 主事研究員 (30225429)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1999: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Central nervous system / Competitive PCR / Cytokine / Autoimmune encephalomyelitis / Glia / STAT / In situ hybridization / in situ RT-PCR |
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| Research Abstract |
To know the role of cytokines in the lesion repair process in the central nervous system (CNS), experimental autoimmune encephalomyelitis (EAE) was induced in rats and the level of pro- and anti-inflammatory cytokine mRNA in the central nervous system (CNS) was quantitated by competitive PCR. In EAE, TNF-α and IFN-γ mRNA were detected mainly at the early stage of the disease, while one of anti-inflammatory cytokines, TGF-β1, peaked at the later stage.
In the next step, we investigated the kinetics and localization of STAT (signal transducer and activators of transcription) mRNA and protein, which is known as a transducing molecule activated after cytokine binding to the cytokine receptor, in the CNS during autoimmune inflammation. It was demonstrated that STAT4 which was expressed in microglia and probably activated by IL-12 plays a pro-inflammatory role and that STAT3 which was activated throughout the disease course and expressed mainly in astrocytes seems to serve as a transducer of anti-inflammatory signals.
Finally, we have performed in situ hybridization to determine the cell that produce the cytokine in the CNS. Since the amount of cytokines in the CNS is low, special care was taken to improve the sensitivity of the probe used in non-radioisotopic hybridization. With this improvement, it was possible to show that microglia express TNF-α while neuron and astrocytes express TGF-β1.
Taking all these findings together, the following mechanism of the region repair is suggested. Soon after the infiltration of autoreactive T cells in the CNS, microglia are activated by T cells and secrete pro-inflammatory cytokines such as TNF-α to upregulate T cell function and at the same time stimulate the astrocyte which downregulate the inflammatory processes by secreting anti-inflammatory cytokines including TGF-β. The cytokine network regulated by various types of brain cells is critical for the region repair in the CNS.
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