Massive hepatic apoptosis associated with TGF-β1 activation after Fas ligand treatment of IGF binding protein-1-deficient mice
Massive hepatic apoptosis associated with TGF-β1 activation after Fas ligand treatment of IGF binding protein-1-deficient mice
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DOI：
10.1172/jci200316712
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发表时间：
2003-01-01
影响因子：
15.9
通讯作者：
Taub, R
中科院分区：
文献类型：
--
作者：
Leu, JI;Crissey, MAS;Taub, R
由病毒性肝炎或毒性损伤引起的急性肝功能衰竭涉及凋亡和坏死途径。胰岛素样生长因子结合蛋白-1（IGFBP-1）是一种肝细胞源性分泌蛋白，是正常肝再生所必需的。为了确定IGFBP-1是否可以预防直接刺激肝细胞凋亡的肝损伤，用正常亚致死剂量的Fas激动剂处理IGFBP-1（-/-）小鼠、IGFBP-1（+/+）小鼠和用抗IGFBP-1的Ab预处理的小鼠。IGFBP-1缺乏与Fas激动剂治疗3小时内大量肝细胞凋亡和半胱天冬酶激活相关，这可以通过IGFBP-1预处理来纠正。IGFBP-1缺乏的肝脏在Fas激动剂治疗后早期（0.5至1小时）通过整合素受体增强了信号传导，并伴有活化的基质金属蛋白酶-9（MMP-9）升高，MMP-9是纤连蛋白信号传导的已知靶点和TGF-β的激活剂。在Fas激动剂治疗的3小时内，在IGFBP-1缺陷的肝脏中观察到活性TGF-β 1（肝细胞促凋亡原）的表达升高，这与凋亡过程的出现相关。MMP-9和TGF-β 1的表达均被IGFBP-1处理抑制，支持它们在凋亡过程中的作用。IGFBP-1（-/-）小鼠在CCl 4引起的毒性肝损伤模型中也显示损伤增加。这些发现表明IGFBP-1通过降低促凋亡信号的水平在肝脏中作为关键的肝存活因子发挥作用。
Acute liver failure caused by viral hepatitis or toxic damage involves both apoptotic and necrotic pathways. IGF binding protein-1 (IGFBP-1), a hepatocyte-derived secreted protein, is required for normal liver regeneration. To determine whether IGFBP-1 could prevent liver injury that entails direct stimulation of hepatocyte apoptosis, IGFBP-1(-/-) mice, IGFBP-1(+/+) mice, and mice pretreated with Ab's against IGFBP-1 were treated with a normally sublethal dose of Fas agonist. IGFBP-1 deficiency was associated with massive hepatocyte apoptosis and caspase activation within 3 hours of Fas agonist treatment, which could be corrected by pretreatment with IGFBP-1. IGFBP-1-deficient livers had enhanced signaling via the integrin receptor at early times (0.5 to 1 hour) after Fas agonist treatment accompanied by elevated activated matrix metalloproteinase-9 (MMP-9), a known target of fibronectin signaling and activator of TGF-beta. Within 3 hours of Fas agonist treatment, elevated expression of active TGF-beta1, a hepatocyte apoptogen, was observed in IGFBP-1-deficient livers that correlated with the appearance of the apoptotic process. Both MMP-9 and TGF-beta1 expression were suppressed by IGFBP-1 treatment, supporting their role in the apoptotic process. IGFBP-1(-/-) mice also displayed increased injury in a toxic hepatic injury model caused by CCl4. These findings indicate that IGFBP-1 functions as a critical hepatic survival factor in the liver by reducing the level of proapoptotic signals.