State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention , Chang-Bai Rd 155, Beijing 102206, People's Republic of China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University , Hangzhou, 310003, People's Republic of China.
ACS Chem Neurosci. 2017 Nov 15;8(11):2535-2548. doi: 10.1021/acschemneuro.7b00273. Epub 2017 Aug 21.
Transcription factor NF-κB functions as a pleiotropic regulator of target genes controlling physiological function as well as pathological processes of many different diseases, including some neurodegenerative diseases. However, the role of NF-κB in the pathogenesis of prion disease remains ambiguous. In this study, the status of NF-κB (p65) in a prion-infected cell line SMB-S15 was first evaluated. Significantly lower levels of p65 and the phosphorylated form of p65 (p-p65) were detected in SMB-S15 cells, compared with its normal partner cell line SMB-PS. Markedly slower responses of the NF-κB system to the stimulation of TNF-α were observed in SMB-S15 cells. Removal of PrP replication in SMB-S15 cells rescued the expression and activity of NF-κB. However, overexpression of p65 in SMB-S15 cells did not influence the propagation of PrP. Moreover, significant decline of p65 level was also observed in the brain tissues of mice infected with the lysates of SMB-S15 cells and hamsters infected with scrapie agent 263K at terminal stage. Immunofluorescence assays (IFAs) on brain sections from either normal or scrapie-infected rodents revealed colocalization of p65 with neuronal nuclear (NeuN) protein positive cells but not with glial fibrillary acidic protein (GFAP) positive cells. Assays of the agents involving in the regulation of NF-κB showed down-regulated phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB/Akt) both in SMB-S15 cells and in the brains of scrapie-infected rodents. Those data indicate a remarkable repression of the classical NF-κB pathway during prion infection both in vitro and in vivo. The alteration of NF-κB (p65) shows close association with the replication and accumulation of PrP in the cells.
转录因子 NF-κB 作为一个多功能调节因子，可调控控制多种不同疾病（包括一些神经退行性疾病）的生理功能和病理过程的靶基因。然而，NF-κB 在朊病毒病发病机制中的作用仍不明确。在本研究中，首先评估了 NF-κB（p65）在朊病毒感染的 SMB-S15 细胞系中的状态。与正常的配对细胞系 SMB-PS 相比，SMB-S15 细胞中 p65 和磷酸化形式的 p65（p-p65）水平显著降低。在 SMB-S15 细胞中，NF-κB 系统对 TNF-α刺激的反应明显较慢。在 SMB-S15 细胞中去除 PrP 复制可挽救 NF-κB 的表达和活性。然而，在 SMB-S15 细胞中过表达 p65并不影响 PrP 的传播。此外，在感染 SMB-S15 细胞裂解物的小鼠和感染 263K 朊病毒的仓鼠的脑组织中也观察到 p65 水平显著下降。对正常或感染神经退行性病变的啮齿动物脑组织的免疫荧光分析（IFAs）显示，p65 与神经元核（NeuN）蛋白阳性细胞而非神经胶质纤维酸性蛋白（GFAP）阳性细胞共定位。对涉及 NF-κB 调节的试剂的检测显示，PI3K 和蛋白激酶 B（PKB/Akt）在 SMB-S15 细胞和感染朊病毒的啮齿动物脑组织中均下调。这些数据表明，在体外和体内，朊病毒感染时经典 NF-κB 途径受到显著抑制。NF-κB（p65）的改变与细胞中 PrP 的复制和积累密切相关。
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