A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation
A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation
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DOI：
10.1016/j.hep.2003.09.020
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发表时间：
2003-12-01
期刊：
影响因子：
13.5
通讯作者：
Neurath, MF
中科院分区：
文献类型：
--
作者：
Siebler, J;Wirtz, S;Neurath, MF
TH1细胞因子被认为参与了t细胞介导的肝损伤和炎症的发病机制。然而，参与这种损伤的分子信号通路仍然知之甚少。在本研究中，我们利用新创建的STAT1转基因小鼠以及STAT1和T-bet缺失小鼠，研究了STAT1/T-bet信号通路在cona诱导的t细胞介导的肝脏炎症小鼠模型中的作用。Con A诱导的肝损伤与肝脏pSTAT1和T-bet水平升高有关。此外，功能研究表明STAT1在Con a诱导的肝损伤中具有致病作用，因为在CD2启动子/增强子结构的控制下，过度表达STAT1的转基因小鼠显示干扰素γ (ifn - γ)和IRF-1水平升高，并且在给药Con a后肝损伤显著增强。一致地，我们观察到STAT1缺陷和t- β缺陷小鼠都能免受这种t细胞依赖性肝损伤。总之，这些发现表明STAT1/T-bet信号通路在t细胞介导的肝脏病理Con a模型中对t细胞活化具有关键的致病作用。
TH1 cytokines have been suggested to contribute to the pathogenesis of T-cell-mediated liver injury and inflammation. However, the molecular signaling pathways involved in such injury are still poorly understood. In the present study, we investigated the role of the STAT1/T-bet signaling pathway in a murine model of T-cell-mediated liver inflammation induced by the application of concanavalin A (Con A) using newly created STAT1 transgenic mice as well as STAT1- and T-bet-deficient mice. Liver injury induced by Con A was associated with an increase of both pSTAT1 and T-bet levels in the liver. Furthermore, functional studies suggested a pathogenic role for STAT1 in Con A-induced liver injury, because transgenic mice overexpressing STAT1 under the control of the CD2 promoter/enhancer construct showed elevated interferon gamma (IFN-gamma) and IRF-1 levels as well as significantly augmented liver injury following administration of Con A. Consistently, we observed that both STAT1-deficient and T-bet-deficient mice were protected from such T-cell- dependent liver injury. In conclusion, these findings suggest a key pathogenic role for the STAT1/T-bet signaling pathway for T-cell activation in the Con A model of T-cell-mediated liver pathology.