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.
Keywords: Apoptosis; NSC; TNF-α; p38 MAPK.