PTEN-mediated Akt/β-catenin/Foxo1 signaling regulates innate immune responses in mouse liver ischemia/reperfusion injury.
PTEN-mediated Akt/β-catenin/Foxo1 signaling regulates innate immune responses in mouse liver ischemia/reperfusion injury.
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DOI：
10.1002/hep.25958
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发表时间：
2013-01
期刊：
影响因子：
13.5
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Kamo, Naoko;Ke, Bibo;Busuttil, Ronald W.;Kupiec-Weglinski, Jerzy W.
10号染色体上的磷酸酶和张力蛋白同源物缺失（PTEN）与磷酸肌醇3-激酶（PI 3 K）及其直接下游靶基因Akt相反地调节先天性免疫应答。Forkhead box O（Foxo）转录因子在组织发育、免疫稳态和细胞存活的调节中是必不可少的。本研究旨在探讨PTEN介导的Akt/β-catenin/Foxo 1信号传导在肝脏部分热缺血90分钟后诱导的肝脏炎症损伤小鼠模型中调节体内和体外先天免疫反应的作用。6小时再灌注（IRI）。我们发现，用小干扰RNA（siRNA）敲低PTEN可促进Akt/β-catenin/Foxo 1信号传导，从而抵抗肝脏IR损伤，局部增强抗凋亡功能，并下调先天性TLR 4表达。特异性PI 3 K阻断抑制Akt/β-连环蛋白信号传导，增加Foxo 1介导的TLR 4驱动的局部炎症，并重建肝脏IRI的主要特征。此外，在LPS刺激的小鼠骨髓源性巨噬细胞中敲低PTEN，增强β-catenin活性，这反过来提供了对Foxo 1功能的负调节反馈，导致TLR 4和NF-κB的抑制，最终抑制体外促炎细胞因子程序。结论：我们的新发现证实了PTEN介导的Akt/β-catenin/Foxo 1轴是小鼠肝脏先天性炎症反应的关键调节因子。通过鉴定PTEN介导的Akt/β-catenin/Foxo 1信号转导在TLR 4先天免疫调节中的分子机制，我们的研究为新的治疗方法提供了理论基础，以管理IR应激肝脏中的炎症损伤。
The phosphatase and tensin homolog delete on chromosome 10 (PTEN) regulates innate immune responses inversely with phosphoinositide 3-kinase (PI3K) and its direct downstream target gene, Akt. The Forkhead box O (Foxo) transcription factors are essential in the regulation of tissue development, immune homeostasis and cell survival. This study was designed to investigate the role of PTEN-mediated Akt/β-catenin/Foxo1 signaling in the regulation of in vivo and in vitro innate immune responses in a mouse model of hepatic inflammatory injury induced by 90 min of liver partial warm ischemia followed by 6 h of reperfusion (IRI). We found that knockdown of PTEN with small interfering RNA (siRNA) promoted Akt/β-catenin/Foxo1 signaling, leading to the resistance against liver IR-damage, local enhancement of antiapoptotic function, and down-regulation of innate TLR4 expression. A specific PI3K blockade inhibited Akt/β-catenin signaling, increased Foxo1-mediated TLR4-driven local inflammation and recreated cardinal features of liver IRI. Moreover, knockdown of PTEN in LPS-stimulated mouse bone marrow derived-macrophages, enhanced β-catenin activity, which in turn provided a negative regulatory feedback to the Foxo1 function, leading to the inhibition of TLR4 and NF-κB, with ultimate depression of proinflammatory cytokine programs in vitro. Conclusion: our novel findings identify PTEN-mediated Akt/β-catenin/Foxo1 axis as a key regulator of innate inflammatory response in the mouse liver. By identifying molecular mechanisms of PTEN-mediated Akt/β-catenin/Foxo1 signaling in TLR4 innate immune regulation, our study provides the rationale for novel therapeutic approaches to manage inflammation injury in IR-stressed liver.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.2
作者：
Ke, Bibo;Shen, Xiu-Da;Kupiec-Weglinski, Jerzy W.
通讯作者：
Kupiec-Weglinski, Jerzy W.
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