Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia
Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia
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DOI：
10.1523/jneurosci.3792-03.2004
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发表时间：
2004-01-07
影响因子：
5.3
通讯作者：
Nakata, Y
中科院分区：
文献类型：
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作者：
Suzuki, T;Hide, I;Nakata, Y
脑损伤后，损伤细胞释放三磷酸腺苷，激活小胶质细胞。以这种方式激活的小胶质细胞然后释放一系列生物活性物质，其中之一是肿瘤坏死因子(TNF)。肿瘤坏死因子的释放似乎依赖于P2X(7)受体。1，4-diamino-2，3-dicyano-1，4-bis[2-amino-phenylthio]丁二烯(U0126)、[1，9-CD]吡唑-6(2H)-酮(SP600125)和4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)IH-咪唑(SB203580)分别靶向丝裂原活化蛋白激酶(MEK)、c-Jun氨基末端激酶(c-Jun N-末端激酶)和p38，均能有效抑制三磷酸腺苷刺激的小胶质细胞产生肿瘤坏死因子，而U0126和SP600125则强烈抑制肿瘤坏死因子的产生。SB203580不影响肿瘤坏死因子信使核糖核酸水平的升高，但可阻止肿瘤坏死因子信使核糖核酸在胞浆内积聚。P2X(7)受体阻断剂亮蓝G和4-氨基-5-(4-氯苯基)-7-(叔丁基)吡唑并[3，4-D]嘧啶分别能抑制ATP诱导的JNK和p38[但不能抑制细胞外信号调节激酶(ERK)]的激活。最重要的是，我们发现，用P2X(7)激动剂2‘-3’-O-(苯甲酰-苯甲酰基)ATP处理神经元-小胶质细胞共培养的小胶质细胞可显著减少谷氨酸诱导的神经细胞死亡，并且肿瘤坏死因子-α转换酶抑制剂或抗肿瘤坏死因子容易抑制这一结果所暗示的保护作用。综上所述，这些发现表明ERK和JNK都参与了肿瘤坏死因子mRNA的表达调控，p38参与了肿瘤坏死因子mRNA的核质转运，而蛋白酪氨酸激酶(PTK)可能是src家族的成员，作用于P2X(7)受体的下游，激活JNK和p38。最后，我们的数据表明，P2X(7)受体激活的小胶质细胞保护神经元免受谷氨酸毒性，主要是因为它们能够释放肿瘤坏死因子。
After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis factor (TNF). The release of TNF appears to be dependent on the P2X(7) receptor. The inhibitors 1,4-diamino-2,3-dicyano-1,4-bis[2-amino-phenylthio] butadiene (U0126), anthra[ 1,9-cd] pyrazol-6(2H)-one (SP600125), and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) IH-imidazole (SB203580), which target MEK (mitogen-activated protein kinase kinase), JNK (c-Jun N-terminal kinase), and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X(7) receptor blocker, and by genistein and 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-D] pyrimidine, which are general and src-family-specific tyrosine kinase inhibitors, respectively. Most important, we found that treatment of the microglia in neuron - microglia cocultures with the P2X(7) agonist 2'-3'-O-(benzoyl-benzoyl) ATP led to significant reductions in glutamate-induced neuronal cell death, and that either TNF-alpha converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Together, these findings indicate that both ERK and JNK are involved in the regulation of TNF mRNA expression, that p38 is involved in the nucleocytoplasmic transport of TNF mRNA, and that a PTK ( protein tyrosine kinase), possibly a member of the src family, acts downstream of the P2X(7) receptor to activate JNK and p38. Finally, our data suggest that P2X(7) receptor-activated microglia protect neurons against glutamate toxicity primarily because they are able to release TNF.