Cyclooxygenase-2 and presenilin-1 gene expression induced by interleukin-1β and amyloid β42 peptide is potentiated by hypoxia in primary human neural cells
Cyclooxygenase-2 and presenilin-1 gene expression induced by interleukin-1β and amyloid β42 peptide is potentiated by hypoxia in primary human neural cells
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DOI：
10.1074/jbc.m203201200
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发表时间：
2002-08-16
影响因子：
4.8
通讯作者：
Lukiw, WJ
中科院分区：
文献类型：
--
作者：
Bazan, NG;Lukiw, WJ
环氧合酶 2 (COX-2) 和早老素 1 (PS1) 产生的脂质信使和淀粉样β (Abeta) 肽介导阿尔茨海默病 (AD) 大脑中的促炎信号传导和神经变性。这项研究提供的数据表明，COX-2 和 PS1 基因各自转录稀有、高度不稳定的 RNA 种类，这些 RNA 种类在原代培养的人类神经 (HN) 细胞中表现出早期反应基因行为，在人类神经发育过程中下调，在 AD 新皮质和海马 CA1 中上调。 IL-1beta 和淀粉样蛋白 beta42 肽 [IL-1beta+Abeta42] 一起协同激活 COX-2 和 PS1 基因表达，随后 AP1-、STAT1alpha-、特别是 NF-kappaBp50/p65- 和 HIF-1alpha-DNA 结合增加。这些事件因缺氧而显着增强，并被抗氧化剂α-苯基-N-叔丁基硝酮阻断。广泛的转录分析进一步表明，缺氧诱导、[IL-1beta+Abeta42]处理的 HN 细胞表现出对 COX-2 和 PS1 以及促炎基因家族（包括 NF-kappaBp50/p105、IL-1beta 前体和胞质磷脂酶 A(2) 基因）的强烈诱导。这些发现表明一种新的[IL-1beta+Abeta42]介导的、缺氧增强的、游离的。自由基触发的基因程序驱动炎症基因信号传导，并提出了衰老过程中缺氧偶尔导致淀粉样蛋白生成、炎症和 AD 病理生理学的机制。
Lipid messengers and amyloid beta (Abeta) peptides generated by cyclooxygenase-2 (COX-2) and presenilin-1 (PS1) mediate pro-inflammatory signaling and neural degeneration in Alzheimer's disease (AD) brain. This study provides data showing that the COX-2 and PS1 genes each transcribe rare, highly labile RNA species that display early response gene behavior in human neural (HN) cells in primary culture, down-regulation during human neural development, and up-regulation in AD neocortex and hippocampal CA1. Together, interleukin-1beta and amyloid beta42 peptide [IL-1beta+Abeta42] synergistically activated COX-2 and PS1 gene expression preceded by increases in AP1-, STAT1alpha-, and in particular NF-kappaBp50/p65- and HIF-1alpha-DNA binding. These events were markedly potentiated by hypoxia and blocked by the antioxidant alpha-phenyl-N-tent-butyl nitrone. Broad transcription profiling further indicated that hypoxia-induced, [IL-1beta+Abeta42]-treated HN cells display robust induction of COX-2 and PS1 as well as a pro-inflammatory gene family that includes NF-kappaBp50/p105, IL-1beta precursor, and cytosolic phospholipase A(2) genes. These findings indicate a novel [IL-1beta+Abeta42]-mediated, hypoxia-enhanced, free. radical-triggered gene program that drives inflammatory gene signaling and suggest a mechanism by which hypoxia during aging contributes episodically to amyloidogenesis, inflammation, and AD pathophysiology.