Haga Sanae, Terui Keita, Zhang Hui Qi, Enosawa Shin, Ogawa Wataru, Inoue Hiroshi, Okuyama Torayuki, Takeda Kiyoshi, Akira Shizuo, Ogino Tetsuya, Irani Kaikobad, Ozaki Michitaka
Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, Japan.
J Clin Invest. 2003 Oct;112(7):989-98. doi: 10.1172/JCI17970.
Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration. In order to investigate the hepatoprotective effects of Stat3, we examined whether Stat3 protects against Fas-mediated liver injury in the mouse. A constitutively activated form of Stat3 (Stat3-C) was adenovirally overexpressed in mouse liver by intravenous injection, and then a nonlethal dose of Fas agonist (Jo2) was injected intraperitoneally into the mouse (0.3 microg/g body wt). Stat3-C dramatically suppressed both apoptosis and necrosis induced by Jo2. In contrast, liver-specific Stat3-knockout mice failed to survive following Jo2 injection. Stat3-C upregulated expression of FLICE inhibitor protein (FLIP), Bcl-xL, and Bcl-2, and accordingly downregulated activities of FLICE and caspase-3 that were redox-independent. Interestingly, Stat3-C also upregulated the redox-associated protein redox factor-1 (Ref-1) and reduced apoptosis in liver following Jo2 injection by suppressing oxidative stress and redox-sensitive caspase-3 activity. These findings indicate that Stat3 activation protects against Fas-mediated liver injury by inhibiting caspase activities in redox-dependent and -independent mechanisms.
信号转导及转录激活因子3(Stat3)是参与肝脏发育和再生起始过程的最重要分子之一。为了研究Stat3的肝脏保护作用,我们检测了Stat3是否能保护小鼠免受Fas介导的肝损伤。通过静脉注射,以腺病毒介导的方式在小鼠肝脏中过表达组成型激活形式的Stat3(Stat3-C),然后向小鼠腹腔注射非致死剂量的Fas激动剂(Jo2,0.3微克/克体重)。Stat3-C显著抑制了Jo2诱导的细胞凋亡和坏死。相反,肝脏特异性Stat3基因敲除小鼠在注射Jo2后未能存活。Stat3-C上调了FLICE抑制蛋白(FLIP)、Bcl-xL和Bcl-2的表达,相应地下调了不依赖氧化还原的FLICE和caspase-3的活性。有趣的是,Stat3-C还上调了与氧化还原相关的蛋白氧化还原因子1(Ref-1),并通过抑制氧化应激和氧化还原敏感的caspase-3活性,减少了Jo2注射后肝脏中的细胞凋亡。这些发现表明,Stat3激活通过在依赖氧化还原和不依赖氧化还原的机制中抑制caspase活性,从而保护小鼠免受Fas介导的肝损伤。