HO-1-STAT3 axis in mouse liver ischemia/reperfusion injury: regulation of TLR4 innate responses through PI3K/PTEN signaling.
HO-1-STAT3 axis in mouse liver ischemia/reperfusion injury: regulation of TLR4 innate responses through PI3K/PTEN signaling.
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小鼠肝脏缺血/再灌注损伤中的 HO-1-STAT3 轴：通过 PI3K/PTEN 信号传导调节 TLR4 先天反应。
DOI：
10.1016/j.jhep.2011.05.023
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发表时间：
2012-02
影响因子：
25.7
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Ke, Bibo;Shen, Xiu-Da;Ji, Haofeng;Kamo, Naoko;Gao, Feng;Freitas, Maria Cecilia S.;Busuttil, Ronald W.;Kupiec-Weglinski, Jerzy W.
信号转导和转录激活子3(STAT3)是抗炎细胞因子信号转导的关键介质，在HO-1诱导的细胞保护中起着至关重要的作用。磷脂酰肌醇3-激酶(PI3K)/磷酸酶和张力蛋白10号染色体上同源缺失(PTEN)通路调节多种先天免疫反应。本研究旨在探讨STAT3在HO-1诱导的先天免疫主导性肝缺血/再灌注损伤(IRI)小鼠PI3K/PTEN级联反应中的作用。转导Ad-HO-1的小鼠对肝脏IRI有抵抗力，这种细胞保护作用与肝内PI3K/Akt增加和PTEN表达减少有关。相比之下，接受辅助Ad-HO-1治疗和STAT3基因敲除(SiRNA)的小鼠仍然容易受到IR介导的局部炎症反应和肝细胞损伤的影响。与PI3K/Akt激活后细胞凋亡减少和TLR4表达抑制一致，尽管Ad-HO-1基因转移，但PI3K特异性抑制剂治疗增加了局部炎症和重建的肝脏IRI。与骨髓来源的巨噬细胞平行的体外研究证实，HO-1-STAT3轴诱导的PI3K/Akt以TLR4依赖的方式负调控PTEN的表达。这些发现强调了HO-1诱导的STAT3在调节肝脏IRI级联反应中PI3K/PTEN的作用。激活PI3K/Akt为TLR4驱动的炎症提供负反馈机制。识别先天免疫系统中STAT3调节的分子途径，为管理移植患者的肝脏炎症和IRI的新的治疗方法提供了理论基础。
Signal transducer and activator of transcription 3 (STAT3), a key mediator of anti-inflammatory cytokine signaling, is essential for heme oxygenase-1 (HO-1)-induced cytoprotection. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog delete on chromosome 10 (PTEN) pathways regulate diverse innate immune responses. This study was designed to investigate the role of STAT3 in the regulation of PI3K/PTEN cascade after HO-1 induction in a mouse model of innate immune-dominated liver ischemia/reperfusion injury (IRI). Mice subjected to Ad-HO-1 transfer were resistant to liver IRI, and this cytoprotective effect correlated with increased intrahepatic PI3K/Akt and diminished PTEN expression. In contrast, mice undergoing adjunctive Ad-HO-1 treatment and STAT3 knockdown (siRNA) remained susceptible to IR-mediated local inflammatory response and hepatocellular damage. Consistent with decreased cell apoptosis and inhibited TLR4 expression after PI3K/Akt activation, treatment with specific PI3k inhibitor increased local inflammation and recreated liver IRI despite Ad-HO-1 gene transfer. Parallel in vitro studies with bone marrow derived-macrophages have confirmed that HO-1 - STAT3 axis-induced PI3K/Akt negatively regulated PTEN expression in TLR4-dependent fashion. These findings underscore the role of HO-1 induced STAT3 in modulating PI3K/PTEN in liver IRI cascade. Activating PI3K/Akt provides negative feedback mechanism for TLR4-driven inflammation. Identifying molecular pathways of STAT3 modulation in the innate immune system provides the rationale for novel therapeutic approaches for the management of liver inflammation and IRI in transplant patients.
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DOI：
10.1161/01.atv.0000143096.15099.ce
发表时间：
2004-10-01
影响因子：
8.7
作者：
Schabbauer, G;Tencati, M;Mackman, N
通讯作者：
Mackman, N
影响因子：
30.5
作者：
Arbibe, L;Mira, JP;Knaus, UG
通讯作者：
Knaus, UG
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.
影响因子：
16.8
作者：
Fukao, T;Koyasu, S
通讯作者：
Koyasu, S
影响因子：
8.8
作者：
Kato, H;Amersi, F;Kupiec-Weglinski, JW
通讯作者：
Kupiec-Weglinski, JW