P2Y1 Receptor Signaling Enhances Neuroprotection by Astrocytes Against Oxidative Stress via IL-6 Release in Hippocampal Cultures
P2Y1 Receptor Signaling Enhances Neuroprotection by Astrocytes Against Oxidative Stress via IL-6 Release in Hippocampal Cultures
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DOI：
10.1002/glia.20749
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发表时间：
2009-02-01
期刊：
影响因子：
6.2
通讯作者：
Inoue, Kazuhide
中科院分区：
文献类型：
--
作者：
Fujita, Takumi;Tozaki-Saitoh, Hidetoshi;Inoue, Kazuhide
细胞存活是神经退行性疾病的发作和进展以及随后的病理事件（包括缺血和创伤性脑损伤）中的关键问题。氧化应激是这种病理条件下细胞损伤的主要原因。在这里，我们报告，腺苷5 '-三磷酸（ATP）保护海马星形胶质细胞从过氧化氢（H2 O2）引起的氧化损伤的星形胶质细胞单一培养。ATP的作用可被P2 Y（1）R的选择性拮抗剂或siRNA阻断。有趣的是，在星形胶质细胞-神经元共培养物中，ATP也对H2 O2诱发的神经元细胞死亡产生神经保护作用，而ATP在单一培养物中不产生任何神经保护作用。ATP诱导的神经保护作用可被星形胶质细胞P2 Y（1）R表达的沉默完全抑制，表明ATP通过激活P2 Y（1）R作用于星形胶质细胞并增强其神经保护功能。此外，这种神经保护作用被模仿应用条件培养基从星形胶质细胞，已被ATP刺激，这意味着从星形胶质细胞的扩散因子的参与。我们发现，在纯化的星形胶质细胞培养物和星形胶质细胞-神经元共培养物中，ATP和P2 Y（1）R激动剂2-甲硫腺苷5'二磷酸（2 MeSADP）诱导白细胞介素-6（IL-6）的释放，但这在神经元单一培养物中不发生。此外，外源性IL-6产生神经保护作用，并且在抗IL-6抗体存在下，由P2 Y（1）R刺激的星形胶质细胞诱导的神经保护被阻止。总之，这些结果表明，P2 Y（1）R刺激的星形胶质细胞保护免受氧化应激诱导的神经元损伤，IL-6是星形胶质细胞释放的关键信号分子。因此，星形胶质细胞中P2 Y（1）R的激活可能在病理条件下拯救神经元免于继发性细胞死亡。(C)2008 Wiley-Liss，Inc.
Cell survival is a critical issue in the onset and progression of neurodegenerative diseases and following pathological events including ischemia and traumatic brain injury. Oxidative stress is the main cause of cell damage in such pathological conditions. Here, we report that adenosine 5'-triphosphate (ATP) protects hippocampal astrocytes from hydrogen peroxide (H2O2)-evoked oxidative injury in astrocyte monocultures. The effect of ATP was prevented by a selective antagonist of or siRNAs against P2Y(1)R. Interestingly, in astrocyte-neuron cocultures, ATP also produced neuroprotective effects against H2O2-evoked neuronal cell death, whereas ATP did not produce any neuroprotective effects in monocultures. The ATP-induced neuroprotection in cocultures was completely inhibited by silencing of astrocytic P2Y(1)R expression, indicating that ATP acts on astrocytes and enhances their neuroprotective functions by activating P2Y(1)R. Furthermore, this neuroprotective effect was mimicked by applying conditioned medium from astrocytes that had been stimulated by ATP, implying an involvement of diffusible factors from astrocytes. We found that, in both purified astrocyte cultures and astrocyte-neuronal cocultures, ATP and the P2Y(1)R agonist 2-methylthioadenosine 5' diphosphate (2MeSADP) induced the release of interleukin-6 (IL-6), but this did not occur in neuron monocultures. Moreover, exogenous IL-6 produced a neuroprotective effect, and the neuroprotection induced by P2Y(1)R-stimulated astrocytes was prevented in the presence of an anti-IL-6 antibody. Taken together, these results suggest that P2Y(1)R-stimulated astrocytes protect against neuronal damage induced by oxidative stress, and that IL-6 is a crucial signaling molecule released from astrocytes. Thus, activation of P2Y(1)R in astrocytes may rescue neurons from secondary cell death under pathological conditions. (C) 2008 Wiley-Liss, Inc.