NF-κB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein
NF-κB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein
复制标题
DOI：
10.1111/j.1460-9568.2009.06898.x
复制
发表时间：
2009-09-01
影响因子：
3.4
通讯作者：
Lindholm, Dan
中科院分区：
文献类型：
--
作者：
Kairisalo, Minna;Korhonen, Laura;Lindholm, Dan
X 染色体连锁凋亡抑制蛋白 (XIAP) 是一种增强细胞存活的抗凋亡蛋白。脑源性神经营养因子 (BDNF) 也能促进神经元活力，但 XIAP 和 BDNF 之间的联系仍不清楚。我们在此表明，XIAP 的过度表达会增加转基因小鼠和培养的大鼠海马神经元中的 BDNF，而通过沉默 RNA 下调 XIAP 会减少 BDNF。 XIAP 还刺激 BDNF 信号传导，如 TrkB 受体和下游分子 cAMP 反应元件结合蛋白的磷酸化增加所示。其机制涉及核因子 kappa B (NF-kappa B) 的激活和 NF-kappa B 信号传导的阻断，从而抑制 XIAP 增加的 BDNF 启动子 I 和 IV 活性。在神经元培养物中，XIAP 还上调白细胞介素 (IL)-6，这是一种 NF-kappa B 反应基因。添加 IL-6 会升高神经元中的 BDNF，而与 IL-6 阻断抗体一起孵育会降低神经元中的 BDNF。 BDNF 本身在较高浓度下会激活神经元中的 NF-κ B。数据表明，XIAP 通过增加 BDNF 和 TrkB 活性对海马神经元具有营养作用。结果揭示了大脑中的细胞因子网络，涉及通过 NF-kappa B 系统互连的 BDNF、IL-6 和 XIAP。
X chromosome-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein enhancing cell survival. Brain-derived neurotrophic factor (BDNF) also promotes neuronal viability but the links between XIAP and BDNF have remained unclear. We show here that the overexpression of XIAP increases BDNF in transgenic mice and cultured rat hippocampal neurons, whereas downregulation of XIAP by silencing RNA decreased BDNF. XIAP also stimulated BDNF signaling, as shown by increased phosphorylation of the TrkB receptor and the downstream molecule, cAMP response element-binding protein. The mechanism involved nuclear factor-kappa B (NF-kappa B) activation and blocking of NF-kappa B signaling inhibited the increased activities of BDNF promoters I and IV by XIAP. In neuronal cultures XIAP also upregulated interleukin (IL)-6, which is an NF-kappa B-responsive gene. The addition of IL-6 elevated whereas incubation with IL-6-blocking antibodies reduced BDNF in the neurons. BDNF itself activated NF-kappa B in the neurons at higher concentrations. The data show that XIAP has trophic effects on hippocampal neurons by increasing BDNF and TrkB activity. The results reveal a cytokine network in the brain involving BDNF, IL-6 and XIAP interconnected via the NF-kappa B system.