SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells
SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells
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DOI：
10.1016/j.bbrc.2012.09.042
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发表时间：
2012-10-12
影响因子：
3.1
通讯作者：
Koya, Daisuke
中科院分区：
文献类型：
--
作者：
Takeda-Watanabe, Ai;Kitada, Munehiro;Koya, Daisuke
炎症在动脉粥样硬化中起着至关重要的作用。单核细胞/巨噬细胞是参与动脉粥样硬化形成中的炎性过程的一些细胞。自噬对炎症等细胞应激发挥保护作用，并受营养传感途径的调节。营养感应途径包括SIRT 1，一种NAD（+）依赖性组蛋白脱乙酰酶，其涉及多种细胞过程的调节，包括炎症和自噬。SIRT 1功能障碍促进单核细胞/巨噬细胞自噬相关炎症调节的机制尚不清楚。在本研究中，我们证明了用2-1（2-羟基萘-1-基亚甲基）氨基-N-（1-苯乙基）苯甲酰胺（Sirtinol），SIRT 1的化学抑制剂，通过核因子（NF）-κ B信号传导激活诱导炎症相关基因如肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6的过表达，这与自噬功能障碍有关，如通过THP-1细胞中p62/Sqstm 1积累和轻链（LC）3 II表达降低所示。自噬抑制剂3-甲基腺嘌呤也诱导炎症相关的NF-κ B活化。在p62/Sqstml敲减细胞中，通过NF-κ B活化的Sirtinol诱导的炎症被阻断。此外，SIRT 1的抑制涉及雷帕霉素（mTOR）通路的哺乳动物靶点的激活，并且涉及5 '-AMP激活激酶（AMPK）激活的降低，导致自噬的损害。mTOR抑制剂雷帕霉素消除了Sirtinol诱导的炎症和与p62/Sqstm 1积累相关的NF-κ B活化。总之，SIRT 1失活通过NF-κ B激活诱导炎症，并通过营养感应途径如mTOR和AMPK途径在THP-1细胞中失调自噬。(C)2012 Elsevier Inc. All rights reserved.
Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are some of the cells involved in the inflammatory process in atherogenesis. Autophagy exerts a protective effect against cellular stresses like inflammation, and it is regulated by nutrient-sensing pathways. The nutrient-sensing pathway includes SIRT1, a NAD(+)-dependent histone deacetylase, which is implicated in the regulation of a variety of cellular processes including inflammation and autophagy. The mechanism through which the dysfunction of SIRT1 contributes to the regulation of inflammation in relation to autophagy in monocytes/macrophages is unclear. In the present study, we demonstrate that treatment with 2-1(2-Hydroxynaphthalen-1-ylmethylene)aminol-N-(1-phenethyl)benzamide (Sirtinol), a chemical inhibitor of SIRT1, induces the overexpression of inflammation-related genes such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 through nuclear factor (NF)-kappa B signaling activation, which is associated with autophagy dysfunction, as shown through p62/Sqstm1 accumulation and decreased expression of light chain (LC) 3 II in THP-1 cells. The autophagy inhibitor, 3-methyladenine, also induces inflammation-related NF-kappa B activation. In p62/Sqstml knockdown cells, Sirtinol-induced inflammation through NF-kappa B activation is blocked. In addition, inhibition of SIRT1 is involved in the activation of the mammalian target of rapamycin (mTOR) pathway and is implicated in decreased 5'-AMP activated kinase (AMPK) activation, leading to the impairment of autophagy. The mTOR inhibitor, rapamycin, abolishes Sirtinol-induced inflammation and NF-kappa B activation associated with p62/Sqstm1 accumulation. In summary, SIRT1 inactivation induces inflammation through NF-kappa B activation and dysregulates autophagy via nutrient-sensing pathways such as the mTOR and AMPK pathways, in THP-1 cells. (C) 2012 Elsevier Inc. All rights reserved.