Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Box 957054, Los Angeles, CA 90095, USA.
J Hepatol. 2012 Feb;56(2):359-66. doi: 10.1016/j.jhep.2011.05.023. Epub 2011 Jul 12.
BACKGROUND & AIMS: 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).
Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6h of reperfusion.
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.
信号转导子和转录激活子 3（STAT3）是抗炎细胞因子信号的关键介质，对于血红素加氧酶-1（HO-1）诱导的细胞保护至关重要。磷酸肌醇 3-激酶（PI3K）/磷酸酶和张力蛋白同源物缺失于染色体 10（PTEN）途径调节多种固有免疫反应。本研究旨在研究 HO-1 诱导后 STAT3 在固有免疫主导的肝缺血/再灌注损伤（IRI）小鼠模型中对 PI3K/PTEN 级联的调节作用。
对 C57BL/6 小鼠的左、中叶肝进行部分热缺血 90min，再灌注 6h。
转导 Ad-HO-1 的小鼠对肝 IRI 具有抗性，这种细胞保护作用与肝内 PI3K/Akt 增加和 PTEN 表达减少相关。相反，接受 Ad-HO-1 治疗和 STAT3 敲低（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，尽管转导了 Ad-HO-1 基因，但特异性 PI3K 抑制剂的治疗增加了局部炎症并重新产生了肝 IRI。骨髓来源的巨噬细胞的平行体外研究证实，HO-1-STAT3 轴诱导的 PI3K/Akt 以 TLR4 依赖的方式负调控 PTEN 表达。
这些发现强调了 HO-1 诱导的 STAT3 在调节肝 IRI 级联中的作用。激活 PI3K/Akt 为 TLR4 驱动的炎症提供了负反馈机制。鉴定 STAT3 调节在固有免疫系统中的分子途径为移植患者肝炎症和 IRI 的治疗提供了新的治疗方法。
