Multi-targeted neuroprotection by the HSV-2 gene ICP10PK includes robust bystander activity through PI3-K/Akt and/or MEK/ERK-dependent neuronal release of vascular endothelial growth factor and fractalkine.
Multi-targeted neuroprotection by the HSV-2 gene ICP10PK includes robust bystander activity through PI3-K/Akt and/or MEK/ERK-dependent neuronal release of vascular endothelial growth factor and fractalkine.
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DOI：
10.1111/j.1471-4159.2009.06475.x
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发表时间：
2010-02
影响因子：
4.7
通讯作者：
Aurelian L
中科院分区：
文献类型：
--
作者：
Laing JM;Smith CC;Aurelian L
感染HSV-2抗凋亡基因ICP10PK ΔRR载体的海马培养物在多种损伤引发的细胞死亡中存活。存活包括对未感染神经元的强大保护，但这种旁观者活动的机制尚不清楚。在这里，我们报道了ICP10PK+神经元释放可溶性因子，保护未感染的神经元免受NMDA和MPP+诱导的凋亡。释放依赖于ICP10PK介导的Ras信号通路MEK/ERK和PI3-K/Akt的激活，在感染ICP10PK阴性载体ΔPK的培养中未见这种情况。释放的神经保护因子包括血管内皮生长因子（VEGF）和fractalkine，在条件培养基中，感染ΔRR （NCMΔRR）的海马培养物的水平明显高于ΔPK或磷酸盐缓冲盐水（模拟感染）。VEGF中和抑制NCMΔRR的神经保护活性，提示VEGF的保护作用是通过神经元间的串扰实现的。NCMΔRR也刺激小胶质细胞释放升高的IL-10水平和降低的TNF-α水平，这对未感染的神经元具有保护作用。这些释放模式在给予NCMΔRR的小胶质细胞中未见，其中fractalkine被中和，表明fractalkine的保护功能是通过神经元与小胶质细胞的双向通信。总的来说，这些数据表明ΔRR是一种多靶点策略来拯救神经元免受兴奋性毒性损伤。
Hippocampal cultures infected with the ΔRR vector for the HSV-2 anti-apoptotic gene ICP10PK survive cell death triggered by a wide variety of insults. Survival includes robust protection of uninfected neurons, but the mechanism of this bystander activity is still unclear. Here we report that ICP10PK+ neurons release soluble factors that protect uninfected neurons from NMDA and MPP+-induced apoptosis. Release depends on ICP10PK-mediated activation of the Ras signaling pathways MEK/ERK and PI3-K/Akt, and it was not seen for cultures infected with the ICP10PK negative vector ΔPK. The released neuroprotective factors include vascular endothelial growth factor (VEGF) and fractalkine, the levels of which were significantly higher in conditioned media from hippocampal cultures infected with ΔRR (NCMΔRR) than ΔPK or phosphate-buffered saline (mock infection). VEGF neutralization inhibited the neuroprotective activity of NCMΔRR, indicating that the VEGF protective function is through neuron-neuron cross-talk. NCMΔRR also stimulated microglia to release increased levels of IL-10 and decreased levels of TNF-α that were protective for uninfected neurons. These release patterns were not seen for microglia given NCMΔRR in which fractalkine was neutralized, indicating that the fractalkine protective function is through bidirectional neuron-microglia communication. Collectively, the data indicate that ΔRR is a multiple target strategy to rescue neurons from excitotoxic injury.
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DOI：
10.1073/pnas.97.18.10242
发表时间：
2000-08-29
影响因子：
11.1
作者：
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通讯作者：
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