High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-κB activation
High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-κB activation
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DOI：
10.1038/75057
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发表时间：
2000-05-01
期刊：
影响因子：
82.9
通讯作者：
Ben-Neriah, Y
中科院分区：
文献类型：
--
作者：
Lavon, I;Goldberg, I;Ben-Neriah, Y
基于核因子-kappa B在免疫和炎症反应中的重要作用以及它在正常和恶性细胞中的凋亡挽救功能，该转录因子的抑制剂是治疗从支气管哮喘到癌症的广泛疾病的潜在疗法(1，2)。然而，鉴于核因子-kappa B在胚胎肝脏中的基本功能(3-6)，确定其在胚胎发育后在肝脏中的必要性是重要的。核因子-kappa B通常被其抑制物I kappa B保留在细胞质中，当细胞刺激时，通过依赖于磷酸化的泛素降解消除该抑制物[7]。在这里，我们以诱导的方式将抗降解的I kappa Bα转基因引导到小鼠肝细胞，并使用各种手段显示出显著的组织特异性，包括一种新的活体动物成像方法。转基因表达导致核因子-kappaB的激活受阻，但即使实施了15个月以上，也没有出现肝功能障碍的迹象。然而，转基因表达的小鼠对严重的免疫挑战和系统性细菌感染都非常脆弱。尽管有完整的免疫细胞和炎症细胞，但这些小鼠无法清除肝脏中的单核细胞增多性李斯特菌，并死于败血症。这些发现表明，在某些全身性感染中，肝细胞通过激活核因子-kappaB发挥重要作用，可能是通过协调肝脏的天然免疫。
Based on the essential involvement of NF-kappa B in immune and inflammatory responses and its apoptosis-rescue function in normal and malignant cells, inhibitors of this transcription factor are potential therapeutics for the treatment of a wide range of diseases, from bronchial asthma to cancer(1,2). Yet, given the essential function of NF-kappa B in the embryonic liver(3-6), it is important to determine its necessity in the liver beyond embryogenesis. NF-kappa B is normally retained in the cytoplasm by its inhibitor I kappa B, which is eliminated upon cell stimulation through phosphorylation-dependent ubiquitin degradation(7). Here, we directed a degradation-resistant I kappa B alpha transgene to mouse hepatocytes in an inducible manner and showed substantial tissue specificity using various means, including a new method for live-animal imaging. Transgene expression resulted in obstruction of NF-kappa B activation, yet produced no signs of liver dysfunction, even when implemented over 15 months. However, the transgene-expressing mice were very vulnerable both to a severe immune challenge and to a systemic bacterial infection. Despite having intact immunocytes and inflammatory cells, these mice were unable to clear Listeria monocytogenes from the liver and succumbed to sepsis. These findings indicate the essential function of the hepatocyte through NF-kappa B activation in certain systemic infections, possibly by coordinating innate immunity in the liver.