Inhibition of Double-Stranded RNA-Dependent Protein Kinase Strongly Decreases Cytokine Production and Release in Peripheral Blood Mononuclear Cells from Patients with Alzheimer's Disease
Inhibition of Double-Stranded RNA-Dependent Protein Kinase Strongly Decreases Cytokine Production and Release in Peripheral Blood Mononuclear Cells from Patients with Alzheimer's Disease
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DOI：
10.3233/jad-2010-100258
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Paccalin, Marc
中科院分区：
文献类型：
--
作者：
Couturier, Julien;Page, Guylene;Paccalin, Marc
阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，是老年人最常见的痴呆症。在AD的致病机制中，描述了慢性全身性炎症，其特征在于外周血单核细胞（PBMC）大量产生促炎细胞因子，这可能导致免疫应答改变和神经变性恶化。研究还报告了AD患者PBMC中双链RNA依赖性蛋白激酶（PKR）活化增加。有趣的是，PKR可能参与NF-κ B激活，导致多种细胞因子的产生。我们建议通过用PKR特异性抑制剂治疗25例AD患者的PBMC来减少促炎细胞因子的产生和释放。我们的研究结果表明，PKR抑制大大降低肿瘤坏死因子α，白细胞介素（IL）-1 α，IL-1 β，IL-6的生产和释放，但不影响趋化因子RANTES。此外，抑制促炎因子与预防caspase-3活化相关。提示在外周水平特异性抑制PKR可减轻AD的炎症反应。
Alzheimer's disease (AD), a neurodegenerative disorder, is themost common formof dementia in the elderly individuals. Among the pathogenic mechanisms in AD, chronic systemic inflammation is described and characterized by massive production of proinflammatory cytokines by peripheral blood mononuclear cells (PBMCs), which may contribute to an altered immune response and exacerbation of neurodegeneration. Studies have also reported increased double-stranded RNA-dependent protein kinase (PKR) activation in the PBMCs of patients with AD. Interestingly, PKR could be involved in NF-kappa B activation, leading to production of a wide range of cytokines. We proposed to decrease proinflammatory cytokines production and release by treating the PBMCs in 25 patients with AD with a specific inhibitor of PKR. Our results showed that PKR inhibition greatly decreased tumor necrosis factor alpha, interleukin (IL)-1 alpha, IL-1 beta, and IL-6 production and release but did not affect the chemokine RANTES. Moreover, inhibition of the proinflammatory factors was correlated with prevention of caspase-3 activation. These results indicated that specific inhibition of PKR at the peripheral level might decrease the inflammatory response in AD.