TNF-alpha preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein.
TNF-alpha preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein.
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DOI：
10.4049/jimmunol.0801892
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发表时间：
2009-08-01
期刊：
影响因子：
--
通讯作者：
Pahan K
中科院分区：
文献类型：
--
作者：
Saha RN;Ghosh A;Palencia CA;Fung YK;Dudek SM;Pahan K
尽管是一种促炎细胞因子，但肿瘤坏死因子-α（TNF-α）使神经元对各种毒性损伤具有预处理作用。然而，对潜在的分子机制知之甚少。本研究探讨CREB结合蛋白（CBP）在促进TNF-α介导的神经元预适应中的重要作用。用纤维状淀粉样蛋白β 1-42（Aβ）处理大鼠原代神经元导致CBP蛋白的丢失。然而，这种损失被TNF-α预处理所补偿，因为神经元CBP的表达响应于TNF-α处理而上调。TNF-α仅在神经元中诱导CBP的产生，而在星形胶质细胞和小胶质细胞中不诱导CBP的产生，且CBP的产生依赖于转录因子NF-κB的激活。有趣的是，CBP的反义敲除消除了TNF-α介导的神经元对Aβ和谷氨酸毒性的预处理。同样，在体内，在小鼠皮质中预先给予TNF-α可防止Aβ诱导的细胞凋亡和胆碱乙酰转移酶（ChAT）阳性胆碱能神经元的丢失。然而，cbp反义寡核苷酸联合给药，而不是乱序寡核苷酸，否定了TNF-α对Aβ神经毒性的保护作用。这项研究阐明了TNF-α在增加CBP的神经元特异性表达中的一种新的生物学作用，这种作用可能对神经退行性疾病具有治疗潜力。
Despite being a proinflammatory cytokine, tumor necrosis factor-α (TNF-α) preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF-α-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid-β 1–42 (Aβ) resulted in the loss of CBP protein. However, this loss was compensated by TNF-α preconditioning as the expression of neuronal CBP was upregulated in response to TNF-α treatment. The induction of CBP by TNF-α was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-κB. Interestingly, antisense knockdown of CBP abrogated TNF-α-mediated preconditioning of neurons against Aβ and glutamate toxicity. Similarly in vivo, pre-administration of TNF-α in mouse cortex prevented Aβ-induced apoptosis and loss of choline acetyl transferase (ChAT)-positive cholinergic neurons. However, co-administration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF-α against Aβ neurotoxicity. This study illustrates a novel biological role of TNF-α in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.
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