Multiorgan nuclear factor kappa B activation in a transgenic mouse model of systemic inflammation
Multiorgan nuclear factor kappa B activation in a transgenic mouse model of systemic inflammation
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DOI：
10.1164/ajrccm.162.3.9906129
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发表时间：
2000-09-01
影响因子：
24.7
通讯作者：
Kerr, LD
中科院分区：
文献类型：
--
作者：
Blackwell, TS;Yull, FE;Kerr, LD
我们利用一个转基因小鼠系，在核因子κ B（NF-κ B）依赖性启动子（来自5'人类免疫缺陷病毒-1 [HIV-1]长末端重复序列）的控制下表达Photinus荧光素酶互补DNA（cDNA），以检查NF-κ B激活在细菌内毒素（脂多糖[LPS]）诱导的全身炎症发病机制中的作用。腹腔注射E. coli LPS，这些小鼠表现出时间和剂量依赖性的，器官特异性的荧光素酶表达模式，表明NF-κ B依赖性基因转录在多个器官中被全身性LPS给药瞬时激活。肝中的荧光素酶表达可以通过静脉内施用表达NF-κ B的显性抑制剂（I κ B-alpha DN）的复制缺陷型腺病毒载体来特异性阻断，证实荧光素酶基因表达是该品系小鼠中NF-κ B活化的替代标志物。在用腹膜内LPS治疗后，发现小鼠具有被认为是NF-κ B依赖性的多种细胞因子的增加的肺组织信使RNA（mRNA）表达，以及推测的NF-κ B依赖性细胞因子的升高的血清浓度。在肺组织匀浆中，荧光素酶活性和KC水平之间存在密切的相关性。这些研究表明，用LPS进行的全身性治疗协调了多器官NF-κ B依赖性应答，其可能调节全身性炎症的病理生物学。
We utilized a line of transgenic mice expressing Photinus luciferase complementary DNA (cDNA) under the control of a nuclear factor kappa B (NF-kappa B)-dependent promoter (from the 5' human immunodeficiency virus-1 [HIV-1] long terminal repeat) to examine the role of NF-kappa B activation in the pathogenesis of systemic inflammation induced by bacterial endotoxin (lipopolysaccharide [LPS]). After intraperitoneal injection of E. coli LPS, these mice displayed a time- and dose-dependent, organ-specific pattern of luciferase expression, showing that NF-kappa B-dependent gene transcription is transiently activated in multiple organs by systemic LPS administration. Luciferase expression in liver could be specifically blocked by intravenous administration of replication-deficient adenoviral vectors expressing a dominant inhibitor of NF-kappa B (I kappa B-alpha DN), confirming that luciferase gene expression is a surrogate marker for NF-kappa B activation in this line of mice. After treatment with intraperitoneal LPS, the mice were found to have increased lung tissue messenger RNA (mRNA) expression of a variety of cytokines that are thought to be NF-kappa B-dependent, as well as elevated serum concentrations of presumed NF-kappa B-dependent cytokines. In lung tissue homogenates, a close correlation was identified between luciferase activity and KC levels. These studies show that systemic treatment with LPS orchestrates a multiorgan NF-kappa B-dependent response that likely regulates the pathobiology of systemic inflammation.