title: Tumor Necrosis Factor Alpha Induces Neural Stem Cell Apoptosis Through Activating p38 MAPK Pathway.
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.
authors.affiliation: Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, China.
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Chen
authors.affiliation: Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, China.
authors.forename: Fuxin
authors.initials: F
authors.lastname: Wei
authors.affiliation: Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, China.
authors.forename: Shangbin
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, China. yongwan65@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road, Guangzhou, 510080, China. gzsyliu@tom.com.
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D058953:Neural Stem Cells / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; C093642:SB 203580
keywords: Apoptosis; NSC; TNF-α; p38 MAPK