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首页> 外文期刊>Molecular and Cellular Biology >Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock
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Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock

机译：芳烃受体不足的小鼠对脂多糖诱导的败血性休克的超敏性

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摘要

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is known to mediate a wide variety of pharmacological and toxicological effects caused by polycyclic aromatic hydrocarbons. Recent studies have revealed that AhR is involved in the normal development and homeostasis of many organs. Here, we demonstrate that AhR knockout (AhR KO) mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly due to the dysfunction of their macrophages. In response to LPS, bone marrow-derived macrophages (BMDM) of AhR KO mice secreted an enhanced amount of interleukin-1β (IL-1β). Since the enhanced IL-1β secretion was suppressed by supplementing Plasminogen activator inhibitor-2 (Pai-2) expression through transduction with Pai-2-expressing adenoviruses, reduced Pai-2 expression could be a cause of the increased IL-1β secretion by AhR KO mouse BMDM. Analysis of gene expression revealed that AhR directly regulates the expression of Pai-2 through a mechanism involving NF-κB but not AhR nuclear translocator (Arnt), in an LPS-dependent manner. Together with the result that administration of the AhR ligand 3-methylcholanthrene partially protected mice with wild-type AhR from endotoxin-induced death, these results raise the possibility that an appropriate AhR ligand may be useful for treating patients with inflammatory disorders.
机译：已知芳烃受体（AhR）是一种配体激活的转录因子，可介导由多环芳烃引起的多种药理和毒理作用。最近的研究表明，AhR与许多器官的正常发育和体内稳态有关。在这里，我们证明，AhR基因敲除（AhR KO）小鼠对脂多糖（LPS）引起的败血性休克过敏，主要是由于其巨噬细胞功能障碍。响应LPS，AhR KO小鼠的骨髓巨噬细胞（BMDM）分泌增强量的白介素1β（IL-1β）。由于通过表达Pai-2的腺病毒的转导来补充纤溶酶原激活物抑制剂2（Pai-2）的表达来抑制IL-1β分泌的增强，因此Pai-2的表达降低可能是AhR引起IL-1β分泌增加的原因KO鼠标BMDM。基因表达分析显示，AhR通过涉及NF-κB的机制直接调控Pai-2的表达，但不依赖LPS依赖于AhR核转运子（Arnt）。连同给予AhR配体3-甲基胆碱部分保护具有野生型AhR的小鼠免于内毒素诱导的死亡的结果，这些结果增加了合适的AhR配体可用于治疗炎症患者的可能性。

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