Zhang Lei, Yue Yaping, Ouyang Meishuo, Liu Huaxiang, Li Zhenzhong
Department of Anatomy, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China.
Shandong University School of Public Health, Jinan, 250012, China.
Neurochem Res. 2017 May;42(5):1403-1421. doi: 10.1007/s11064-017-2192-1. Epub 2017 Feb 16.
Upregulation of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-α exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration. The association of IGF-1 with TNF-α and the biological effects, produced by interaction of IGF-1 and TNF-α, on neuronal outgrowth status of primary sensory neurons are still to be clarified. In the present study, using an in vitro model of primary cultured rat dorsal root ganglion (DRG) neurons, we demonstrated that TNF-α challenge at different concentrations elicited diverse biological effects. Higher concentration of TNF-α (10 ng/mL) dampened neurite outgrowth, induced activating transcription factor 3 (ATF3) expression, reduced growth-associated protein 43 (GAP-43) expression, and promoted GAP-43 and ATF3 coexpression, which could be reversed by IGF-1 treatment; while lower concentration of TNF-α (1 ng/mL) promoted neurite sprouting, decreased ATF3 expression, increased GAP-43 expression, and inhibited GAP-43 and ATF3 coexpression, which could be potentiated by IGF-1 supplement. Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-α (10 ng/mL) challenge. In contrast, lower concentration of TNF-α (1 ng/mL) had no significant effect on Akt or S6K activation, and IGF-1 administration activated these two kinases. The effects of IGF-1 were abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These data imply that IGF-1 counteracts the toxic effect of higher concentration of TNF-α, while potentiates the growth-promoting effect of lower concentration of TNF-α, with the node for TNF-α and IGF-1 interaction being the PI3K/Akt/S6K signaling pathway. This study is helpful for interpretation of the association of IGF-1 with TNF-α and the neurobiological effects elicited by interaction of IGF-1 and TNF-α in neurological disorders.
促炎细胞因子肿瘤坏死因子α（TNF-α）的上调参与了多种神经系统疾病的发生和发展。最近的报道对TNF-α仅表现出促炎破坏的有害作用这一概念提出了挑战，并提高了人们对其在特定条件下可能对神经元生长和功能发挥有益作用的认识，这促使我们进一步研究这种细胞因子的作用。胰岛素样生长因子-1（IGF-1）是一种在促进神经元存活、神经元分化、神经突伸长和神经突再生方面具有强大神经保护作用的细胞因子。IGF-1与TNF-α的关联以及IGF-1和TNF-α相互作用对初级感觉神经元神经突生长状态产生的生物学效应仍有待阐明。在本研究中，我们使用原代培养的大鼠背根神经节（DRG）神经元的体外模型，证明了不同浓度的TNF-α刺激会引发不同的生物学效应。较高浓度的TNF-α（10 ng/mL）会抑制神经突生长，诱导激活转录因子3（ATF3）表达，降低生长相关蛋白43（GAP-43）表达，并促进GAP-43和ATF3共表达，而IGF-1处理可逆转这些变化；而较低浓度的TNF-α（1 ng/mL）则促进神经突萌发，降低ATF3表达，增加GAP-43表达，并抑制GAP-43和ATF3共表达，IGF-1补充可增强这些作用。此外，给予IGF-1可恢复被较高浓度的TNF-α（10 ng/mL）刺激所抑制的Akt和p70核糖体蛋白S6激酶（S6K）的激活。相反，较低浓度的TNF-α（1 ng/mL）对Akt或S6K激活无显著影响，而给予IGF-1可激活这两种激酶。IGF-1的作用被磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002消除。这些数据表明，IGF-1可抵消较高浓度TNF-α的毒性作用，同时增强较低浓度TNF-α的促生长作用，TNF-α与IGF-1相互作用的节点是PI3K/Akt/S6K信号通路。本研究有助于解释IGF-1与TNF-α的关联以及IGF-1和TNF-α相互作用在神经系统疾病中引发的神经生物学效应。
