Sulforaphane exerts its anti-inflammatory effect against amyloid-b peptide via STAT-1 dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages
Sulforaphane exerts its anti-inflammatory effect against amyloid-b peptide via STAT-1 dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages
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DOI：
10.1016/j.neurobiolaging.2015.10.016
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发表时间：
2016-02-01
影响因子：
4.2
通讯作者：
Chong, Young Hae
中科院分区：
文献类型：
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作者：
An, Ye Won;Jhang, Kyoung A.;Chong, Young Hae
阿尔茨海默病（AD）是世界上最常见的神经退行性疾病，占老年人痴呆病例的大多数，目前仍缺乏有效的治疗方法。本研究旨在探讨萝卜硫素对人THP-1小胶质样细胞中A β(1-42)单体的抗炎作用。结果表明，萝卜硫素优先抑制主要由A β(1-42)单体诱导的组织蛋白酶b和caspase-1依赖性NLRP3炎症小体的激活，这一作用有效地减少了促炎细胞因子白介素-1b （IL-1b）的过度分泌。随后的机制研究表明，萝卜硫素减轻了A β(1-42)单体诱导的信号换能器和转录-1激活因子的激活。萝卜硫素还增加核因子红系2相关因子2 （Nrf2）核易位，随后血红素加氧酶1 （HO-1）上调。萝卜硫素对A β(1-42)诱导的IL-1b产生的抗炎作用通过小干扰rna介导的Nrf2或HO-1的下调而减弱。此外，萝卜硫素显著降低了阿尔茨海默病大脑颞叶皮层和海马中选择性上调的microRNA-146a水平。上述萝卜硫素的作用被酪氨酸激酶抑制剂、herbimycin A和Nrf2激活剂复制。这些结果表明，转录e1去磷酸化的信号换能器和激活器HO-1及其上游效应物Nrf2在触发萝卜硫素的抗炎信号级联反应中起关键作用，导致a β(1-42)刺激的人小胶质样细胞中IL-1b释放和microRNA-146a产生减少。这些发现表明植物化学萝卜硫素在阿尔茨海默病治疗中具有潜在的应用价值。(C) 2016 Elsevier Inc.版权所有。
Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, accounting for most cases of dementia in elderly individuals, and effective therapies are still lacking. This study was designed to investigate the anti-inflammatory properties of sulforaphane against A beta(1-42) monomers in human THP-1 microglia-like cells. The results showed that sulforaphane preferentially inhibited cathepsin B-and caspase-1-dependent NLRP3 inflammasome activation induced by mostly A beta(1-42) monomers, an effect that potently reduced excessive secretion of the proinflammatory cytokine interleukin-1b (IL-1b). Subsequent mechanistic studies revealed that sulforaphane mitigated the activation of signal transducer and activator of transcription-1 induced by A beta(1-42) monomers. Sulforaphane also increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, which was followed by upregulation of heme-oxygenase 1 (HO-1). The anti-inflammatory effect of sulforaphane on A beta(1-42)-induced IL-1b production was diminished by small interfering RNA-mediated knockdown of Nrf2 or HO-1. Moreover, sulforaphane significantly attenuated the levels of microRNA-146a, which is selectively upregulated in the temporal cortex and hippocampus of AD brains. The aforementioned effects of sulforaphane were replicated by the tyrosine kinase inhibitor, herbimycin A, and Nrf2 activator. These results indicate that signal transducer and activator of transcriptione1 dephosphorylation, HO-1 and its upstream effector, Nrf2, play a pivotal role in triggering an anti-inflammatory signaling cascade of sulforaphane that results in decreases of IL-1b release and microRNA-146a production in A beta(1-42)-stimulated human microglia-like cells. These findings suggest that the phytochemical sulforaphane has a potential application in AD therapeutics. (C) 2016 Elsevier Inc. All rights reserved.