Ishige Kumiko, Tanaka Mikiko, Arakawa Motoki, Saito Hiroshi, Ito Yoshihisa
Department of Pharmacology, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan.
Neurochem Int. 2005 Dec;47(8):545-55. doi: 10.1016/j.neuint.2005.07.010. Epub 2005 Sep 22.
Members of the nuclear factor-kappaB (NF-kappaB)/Rel family (p50, p52, p65 (RelA), RelB and c-Rel) is sequestered in the cytoplasm through its tight association with the inhibitor of NF-kappaB (IkappaB). NF-kappaB has been shown to function as key regulators of either cell death or survival in neurons after activation of the cells by various extracellular signals. In the study presented here, we investigated whether the selective activation of diverse NF-kappaB/Rel family members in HT22 cells might lead to distinct effects on glutamate-induced cell death. Exposing HT22 cells to glutamate, which blocks cystine uptake into the cells via inhibition of the glutamate-cystine antiporter, resulted in a transient activation of IkappaB and NF-kappaB/Rel and caused delayed cell death. Aspirin, which has been shown to block phosphorylation of the IkappaB component of the cytoplasmic NF-kappaB complex, significantly suppressed glutamate-induced cell death, whereas the NF-kappaB decoy oligonucleotide potentiated it. The inhibition of NF-kappaB/Rel protein expression by antisense oligonucleotides showed that p65 is involved in glutamate-mediated cell death, whereas p50 is involved in inhibitory pathways of the cell death. These findings suggest that in HT22 cells, the balance between promoting and presenting cell death to glutamate-induced oxidative stress relies on the activation of distinct NF-kappaB proteins.
核因子-κB（NF-κB）/Rel家族成员（p50、p52、p65（RelA）、RelB和c-Rel）通过与NF-κB抑制因子（IkappaB）紧密结合而被隔离在细胞质中。研究表明，在各种细胞外信号激活细胞后，NF-κB可作为神经元细胞死亡或存活的关键调节因子。在本研究中，我们调查了HT22细胞中不同NF-κB/Rel家族成员的选择性激活是否会对谷氨酸诱导的细胞死亡产生不同影响。将HT22细胞暴露于谷氨酸中，谷氨酸通过抑制谷氨酸-胱氨酸反向转运体来阻断胱氨酸摄入细胞，导致IkappaB和NF-κB/Rel的短暂激活，并引起延迟性细胞死亡。阿司匹林已被证明可阻断细胞质NF-κB复合物中IkappaB成分的磷酸化，它能显著抑制谷氨酸诱导的细胞死亡，而NF-κB诱饵寡核苷酸则会增强这种细胞死亡。反义寡核苷酸对NF-κB/Rel蛋白表达的抑制作用表明，p65参与谷氨酸介导的细胞死亡，而p50参与细胞死亡的抑制途径。这些发现表明，在HT22细胞中，促进和抵御谷氨酸诱导的氧化应激导致的细胞死亡之间的平衡依赖于不同NF-κB蛋白的激活。
