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白细胞介素-11通过STAT3信号通路减轻小鼠肝脏缺血/再灌注损伤

IL-11 Attenuates Liver Ischemia/Reperfusion Injury (IRI) through STAT3 Signaling Pathway in Mice.

作者信息

Zhu Miao, Lu Bo, Cao Qinhong, Wu Zhenfeng, Xu Zhe, Li Weisu, Yao Xuequan, Liu Fukun

机构信息

Department of Surgical Oncology, Affiliated Hospital of Nanjing University of TCM, 155 Hanzhong Road, Nanjing, Jiangsu Province, P. R China.

Department of General Surgery, Yixing People's Hospital, 75 Tongzhenguan Road, Yixing, Jiangsu Province, P. R China.

出版信息

PLoS One. 2015 May 6;10(5):e0126296. doi: 10.1371/journal.pone.0126296. eCollection 2015.

DOI:10.1371/journal.pone.0126296
PMID:25946003
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4422694/
Abstract

BACKGROUND

The protective role of IL-11, an IL-6 family cytokine, has been implicated in ischemia/reperfusion injury (IRI) in the heart and kidney, but its role has not been elucidated in liver IRI. This study was designed to evaluate the effects of IL-11 and its mechanism of action on liver IRI in a mouse model.

METHODS

A partial (70%) warm liver IRI was induced by interrupting the artery/portal vein blood supply to the left/middle liver lobes. IL-11 mRNA expression of ischemic liver after reperfusion was analyzed. Signal transducer and activator of transcription 3 (STAT3) was analyzed following IL-11 treatment in vivo and in vitro. Next, IL-11 was injected intraperitoneally (ip) 1 hour before ischemia. Liver injury was assessed based on serum alanine aminotransferase levels and histopathology. Apoptosis and inflammation were also determined in the ischemic liver. To analyze the role of STAT3 in IL-11 treatment, STAT3 siRNA or non-specific (NS) siRNA was used in vitro and in vivo.

RESULTS

IL-11 mRNA expression was significantly increased after reperfusion in the ischemic liver. STAT3, as a target of IL-11, was activated in hepatocytes after IL-11 treatment in vivo and in vitro. Next, effects of IL-11/STAT3 signaling pathway were assessed in liver IRI, which showed IL-11 treatment significantly attenuated liver IRI, as evidenced by reduced hepatocellular function and hepatocellular necrosis/apoptosis. In addition, IL-11 treatment significantly inhibited the gene expressions of pro-inflammatory cytokines (TNF-α and IL-10) and chemokines (IP-10 and MCP-1). To determine the role of STAT3 in the hepatoprotective effects of IL-11, STAT3 siRNA or NS siRNA was used prior to IL-11 treatment. The results showed STAT3 knockdown abrogated the protective effects of IL-11 in vitro and in vivo.

CONCLUSIONS

This work provides first-time evidence for the protective effect of IL-11 treatment on hepatocyte in liver IRI, through the activation of the STAT3 pathway.

摘要

背景

白细胞介素11（IL-11）是一种白细胞介素6家族细胞因子，其保护作用已被证实与心脏和肾脏的缺血/再灌注损伤（IRI）有关，但在肝脏IRI中的作用尚未阐明。本研究旨在评估IL-11对小鼠肝脏IRI的影响及其作用机制。

方法

通过阻断左/中叶肝脏的动脉/门静脉血液供应诱导部分（70%）温性肝脏IRI。分析再灌注后缺血肝脏中IL-11 mRNA的表达。在体内和体外进行IL-11处理后，分析信号转导和转录激活因子3（STAT3）。接下来，在缺血前1小时腹腔注射IL-11。根据血清丙氨酸转氨酶水平和组织病理学评估肝损伤。还测定了缺血肝脏中的细胞凋亡和炎症情况。为了分析STAT3在IL-11治疗中的作用，在体外和体内使用STAT3小干扰RNA（siRNA）或非特异性（NS）siRNA。

结果

缺血肝脏再灌注后IL-11 mRNA表达显著增加。STAT3作为IL-11的靶点，在体内和体外经IL-11处理后在肝细胞中被激活。接下来，在肝脏IRI中评估IL-11/STAT3信号通路的作用，结果显示IL-11治疗显著减轻了肝脏IRI，肝细胞功能降低以及肝细胞坏死/凋亡减少证明了这一点。此外，IL-11治疗显著抑制促炎细胞因子（TNF-α和IL-10）和趋化因子（IP-10和MCP-1）的基因表达。为了确定STAT3在IL-11肝保护作用中的作用，在IL-11治疗前使用STAT3 siRNA或NS siRNA。结果显示，敲低STAT3消除了IL-11在体外和体内的保护作用。

结论

本研究首次证明了IL-11治疗通过激活STAT3途径对肝脏IRI中的肝细胞具有保护作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/4422694/5f6b3b1bc9e6/pone.0126296.g007.jpg
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