Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
Neuroscience. 2010 Dec 29;171(4):1256-64. doi: 10.1016/j.neuroscience.2010.10.029. Epub 2010 Oct 16.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Fn14) are expressed in neurons. Here we demonstrate that TWEAK induces a dose-dependent increase in neuronal death and that this effect is independent of tumor necrosis factor alpha (TNF-α) and mediated by nuclear factor-kappa B (NF-κB) pathway activation. Incubation with TWEAK induces apoptotic cell death in wild-type (Wt) but not in Fn14 deficient (Fn14(-/-)) neurons. Intracerebral injection of TWEAK induces accumulation of poly(ADP-ribose) polymers (PAR) in Wt but not in Fn14(-/-) mice. Exposure to oxygen-glucose deprivation (OGD) conditions increases TWEAK and Fn14 mRNA expression in Wt neurons, and decreases cell survival in Wt but not in Fn14(-/-) or TWEAK deficient (TWEAK(-/-)) neurons. Experimental middle cerebral artery occlusion (MCAO) increases the expression of TWEAK and Fn14 mRNA and active caspase-3, and the cleavage of poly(ADP-ribose) polymerase-1 (PARP-1) with accumulation of PAR in the ischemic area in Wt but not Fn14(-/-) mice. Together, these results suggest a model where in response to hypoxia/ischemia the interaction between TWEAK and Fn14 in neurons induces PARP-1 activation with accumulation of PAR polymers and cell death via NF-κB pathway activation. This is a novel pathway for hypoxia/ischemia-induced TWEAK-mediated cell death and a potential therapeutic target for ischemic stroke.
肿瘤坏死因子样凋亡弱诱导剂（TWEAK）及其受体成纤维细胞生长因子诱导 14（Fn14）在神经元中表达。在这里，我们证明 TWEAK 诱导神经元死亡呈剂量依赖性增加，并且这种作用独立于肿瘤坏死因子-α（TNF-α），并通过核因子-κB（NF-κB）途径激活介导。用 TWEAK 孵育诱导野生型（Wt）神经元而不是 Fn14 缺失（Fn14（-/-））神经元的凋亡性细胞死亡。脑内注射 TWEAK 在 Wt 但不在 Fn14（-/-）小鼠中诱导聚（ADP-核糖）聚合物（PAR）的积累。暴露于氧葡萄糖剥夺（OGD）条件会增加 Wt 神经元中的 TWEAK 和 Fn14 mRNA 表达，并降低 Wt 神经元的细胞存活率，但不降低 Fn14（-/-）或 TWEAK 缺失（TWEAK（-/-））神经元的细胞存活率。实验性大脑中动脉闭塞（MCAO）增加 TWEAK 和 Fn14 mRNA 的表达以及活性半胱天冬酶-3，并在缺血区 Wt 但不在 Fn14（-/-）小鼠中切割聚（ADP-核糖）聚合酶-1（PARP-1），PAR 聚合物的积累和细胞死亡通过 NF-κB 途径激活。这些结果表明，在缺氧/缺血时，神经元中 TWEAK 和 Fn14 之间的相互作用通过 NF-κB 途径激活诱导 PARP-1 激活，导致 PAR 聚合物的积累和细胞死亡。这是缺氧/缺血诱导的 TWEAK 介导的细胞死亡的新途径，也是缺血性中风的潜在治疗靶点。
