Neuron-specific effects of interleukin-1β are mediated by a novel isoform of the IL-1 receptor accessory protein.
Neuron-specific effects of interleukin-1β are mediated by a novel isoform of the IL-1 receptor accessory protein.
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DOI：
10.1523/jneurosci.4067-11.2011
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发表时间：
2011-12-07
期刊：
影响因子：
--
通讯作者：
Friedman WJ
中科院分区：
文献类型：
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作者：
Huang Y;Smith DE;Ibáñez-Sandoval O;Sims JE;Friedman WJ
在中枢神经系统中，白介素1β(IL-1β)在损伤、感染和疾病过程中被合成和释放，介导炎症反应。然而，在生理条件下，大脑中也存在IL-1，并可以影响海马神经元的功能。在神经元和星形胶质细胞中已经发现了几个细胞特异性的IL-1介导的信号通路和功能，但它们的机制还没有完全确定。在星形胶质细胞中，IL-1β诱导p38MAPK和NF-κB途径调节炎症反应，而在海马神经元中，IL-1ç激活p38而不是NF-κB。此外，IL-1ç在0.01 ng/ml时诱导海马神经元src磷酸化，剂量比用来刺激炎症反应的剂量低1000倍。IL-1信号转导需要IL-1受体(IL-1RI)和IL-1受体辅助蛋白(IL-1RAcP)作为受体伙伴。我们先前报道了IL-1RAcP的一种新的亚型，IL-1RAcPb，仅在中枢神经系统神经元中发现。在这项研究中，我们证明了AcPb以剂量依赖的方式特异性地介导p-Src的IL-1β激活和增强NMDA诱导的小鼠海马神经元的钙内流。缺乏Acpb，但保留ACP，亚型的小鼠在神经元中缺乏对p-Src的IL-1？调节。AcPb对p38MAPK的激活也有调节作用，但对NF-κB信号转导无影响。因此，Acpb在中枢神经系统神经元中的限制性表达，控制着对IL-1ç的特定神经元信号和功能反应。
In the central nervous system (CNS), interleukin-1β (IL-1β) is synthesized and released during injury, infection, and disease, mediating inflammatory responses. However, IL-1ß is also present in the brain under physiological conditions, and can influence hippocampal neuronal function. Several cell-specific IL-1-mediated signaling pathways and functions have been identified in neurons and astrocytes, but their mechanisms have not been fully defined. In astrocytes, IL-1β induced both the p38 MAPK and NF-κB pathways regulating inflammatory responses, however in hippocampal neurons IL-1ß activated p38 but not NF-κB. Additionally, IL-1ß induced Src phosphorylation at 0.01ng/ml in hippocampal neurons, a dose 1000 fold lower than that used to stimulate inflammatory responses. IL-1 signaling requires the type one IL-1 receptor (IL-1RI) and the IL-1 receptor accessory protein (IL-1RAcP) as a receptor partner. We previously reported a novel isoform of the IL-1RAcP, IL-1RAcPb, found exclusively in CNS neurons. In this study, we demonstrate that AcPb specifically mediates IL-1β activation of p-Src and potentiation of NMDA-induced calcium influx in mouse hippocampal neurons in a dose-dependent manner. Mice lacking the AcPb, but retaining the AcP, isoform were deficient in IL-1ß regulation of p-Src in neurons. AcPb also played a modulatory role in the activation of p38 MAPK, but had no effect on NF-κB signaling. The restricted expression of AcPb in CNS neurons, therefore, governs specific neuronal signaling and functional responses to IL-1ß.