Up-regulation of BDNF in Astrocytes by TNF-α: A Case for the Neuroprotective Role of Cytokine
Up-regulation of BDNF in Astrocytes by TNF-α: A Case for the Neuroprotective Role of Cytokine
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DOI：
10.1007/s11481-006-9020-8
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发表时间：
2006-09-01
影响因子：
6.2
通讯作者：
Pahan, Kalipada
中科院分区：
文献类型：
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作者：
Saha, Ramendra N.;Liu, Xiaojuan;Pahan, Kalipada
众所周知，肿瘤坏死因子-α (TNF-α) 参与大脑的生理和病理生理过程，其中这种促炎细胞因子与炎症和存活成分的调节有关。我们报告 TNF-α 上调原代星形胶质细胞中的外显子 IV-bdnf mRNA 和脑源性神经营养因子 (BDNF) 蛋白。在细胞裂解物和细胞外培养基中均可检测到 BDNF 蛋白。 TNF-α 激活 NF-κ B，Delta p65（显性失活突变体）和 NEMO 结合域肽（NF-κ B 抑制剂）抑制 TNF-α 诱导的 BDNF 表达，表明 TNF-α 通过激活 NF-κ B 诱导 BDNF 表达。 TNF-α 诱导 C/EBP β 的激活，并且 BDNF 的表达对 Delta C/EBP β（显性失活突变体）和 ETO（C/EBP β 的抑制剂）的过度表达敏感。在三种 MAP 激酶中，TNF-α 诱导的 BDNF 上调仅对 ERK MAP 激酶抑制剂敏感。然而，ERK MAP 激酶通路与 C/EBP beta 的激活相关，但与 NF-kappa B 的激活无关。总之，这项研究发现了 TNF-α 的一个新特性，即通过 NF-kappa B 和 C/EBP beta 在星形胶质细胞中诱导 BDNF 的表达，这可能与细胞因子的神经营养活性有关。
Tumor necrosis factor-alpha (TNF-alpha) is widely known to be involved in physiological and pathophysiological processes of the brain where this proinflammatory cytokine is implicated with regulation of inflammatory and survival components. We report that TNF-alpha up-regulates exon-IV-bdnf mRNA and brain-derived neurotrophic factor (BDNF) protein in primary astrocytes. The BDNF protein was detectable both in cellular lysate and in the extracellular medium. Activation of NF-kappa B by TNF-alpha and inhibition of TNF-alpha-induced BDNF expression by Delta p65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-kappa B) suggests that TNF-alpha induces BDNF expression through the activation of NF-kappa B. Similarly, TNF-alpha induced the activation of C/EBP beta and the expression of BDNF was sensitive to overexpression of Delta C/EBP beta (a dominant-negative mutant) and ETO (an inhibitor of C/EBP beta). Among three MAP kinases, TNF-alpha-induced BDNF up-regulation was sensitive only to inhibitors of ERK MAP kinase. However, the ERK MAP kinase pathway was coupled to activation of C/EBP beta but not NF-kappa B. Taken together, this study identifies a novel property of TNF-alpha in inducing the expression of BDNF via NF-kappa B and C/EBP beta in astrocytes that may be responsible for neurotrophic activity of the cytokine.