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Tumor Necrosis Factor Alpha Induces Neural Stem Cell Apoptosis Through Activating p38 MAPK Pathway

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Abstract

Tumor necrosis factor alpha (TNF-α) is an essential cytokine that mediates cell death and has been shown to play a potential role in inducing neural stem cell (NSC) apoptosis. We have previously shown that TNF-α antagonist etanercept can suppress the transplanted NSC apoptosis induced by TNF-α in spinal cord injury (SCI) sites; however, the precise molecular mechanism remains unclear. This study aimed to investigate the signaling pathways responsible for TNF-α-induced apoptosis in NSCs. TNF-α treatment impairs cell viability and increases apoptosis of NSCs in concentration- and time-dependent manners. This is embodied in an increase in Bax and cleaved caspase-3 production, coupled with decreased Bcl-2 levels. Additionally, TNF-α remarkably increased the expression of phosphatidylinositol p38 Mitogen-activated protein kinase (p38 MAPK) in NSCs. p38 MAPK regulates apoptosis, acting as an apoptotic signal due to TNF-α exposure. TNF-α-induced apoptosis was significantly alleviated by the p38 MAPK pathway inhibitor SB203580, as well as targeted inhibition of p38 gene in NSCs, or TNF-α antagonist etanercept. These results suggest that TNF-α induces NSCs apoptosis by activating the p38 MAPK signaling pathway and etanercept acts as an effective TNF-α antagonist to prevent p38 MAPK-dependent apoptosis induced by TNF-α in NSCs. Our research represents a potential gene targeting that can prevent unnecessary grafted cell death after transplantation into the SCI models.

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Acknowledgments

This work was supported by grant funds from the National Natural Science Foundation of China (No. 81272007 and 81472069), and the National Science Foundation of Guangdong Province (2016A030313213).

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Correspondence to Yong Wan or Shaoyu Liu.

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Ning-ning Chen and Fuxin Wei are co-first authors.

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11064_2016_2024_MOESM1_ESM.tif

Supplementary Fig. 1 Reduction of cell viability induced by TNF-α in NSCs. (A) Viability of NSCs under the different TNF-α treatment was determined by CCK8 assay. Data were expressed as percentages of the control values .Three independent experiments were carried out. (B) Morphological changes of NSCs induced by various doses of TNF-α treatment for 48 h. Scale bars=500μm, *P<0.05 vs. the 0 groups; #P<0.05 vs. the same concentrations of TNF-α treatment for 24h. (TIF 15046 KB)

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Chen, Nn., Wei, F., Wang, L. et al. Tumor Necrosis Factor Alpha Induces Neural Stem Cell Apoptosis Through Activating p38 MAPK Pathway. Neurochem Res 41, 3052–3062 (2016). https://doi.org/10.1007/s11064-016-2024-8

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  • DOI: https://doi.org/10.1007/s11064-016-2024-8

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