TNF-alpha induces human neural progenitor cell survival after oxygen-glucose deprivation by activating the NF-kappaB pathway

Abstract

Neural progenitor cell (NPC) transplantation has been shown to be beneficial in the ischemic brain. However, the low survival rate of transplanted NPCs in an ischemic microenvironment limits their therapeutic effects. Tumor necrosis factor-alpha (TNF-alpha) is one of the proinflammatory cytokines involved in the pathogenesis of various injuries. On the other hand, several studies have shown that TNF-alpha influences the proliferation, survival, and differentiation of NPCs. Our study investigated the effect of TNF-alpha pretreatment on human NPCs (hNPCs) under ischemia-related conditions in vitro. hNPCs harvested from fetal brain tissue were pretreated with TNF-alpha before being subjected to oxygen-glucose deprivation (OGD) to mimic ischemia in vitro. TNF-alpha pretreatment improved the viability and reduced the apoptosis of hNPCs after OGD. At the molecular level, TNF-alpha markedly increased the level of NF-kappaB signaling in hNPCs, and an NF-kappaB pathway inhibitor, BAY11-7082, completely reversed the protective effects of TNF-alpha on hNPCs. These results suggest that TNF-alpha improves hNPC survival by activating the NF-kappaB pathway. In addition, TNF-alpha significantly enhanced the expression of cellular inhibitor of apoptosis 2 (cIAP2). Use of a lentivirus-mediated short hairpin RNA targeting cIAP2 mRNA demonstrated that cIAP2 protected against OGD-induced cytotoxicity in hNPCs. Our study of intracellular NF-kappaB signaling revealed that inhibition of NF-kappaB activity abolished the TNF-alpha-mediated upregulation of cIAP2 in hNPCs and blocked TNF-alpha-induced cytoprotection against OGD. Therefore, this study suggests that TNF-alpha pretreatment, which protects hNPCs from OGD-induced apoptosis by activating the NF-kappaB pathway, provides a safe and simple approach to improve the viability of transplanted hNPCs in cerebral ischemia.