Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock
Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock
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DOI：
10.1128/mcb.00337-09
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发表时间：
2009-12-15
影响因子：
5.3
通讯作者：
Fujii-Kuriyama, Yoshiaki
中科院分区：
文献类型：
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作者：
Sekine, Hiroki;Mimura, Junsei;Fujii-Kuriyama, Yoshiaki
芳烃受体 (AhR) 是一种配体激活的转录因子，已知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 参与许多器官的正常发育和稳态。在这里，我们证明 AhR 敲除（AhR KO）小鼠对脂多糖（LPS）诱导的败血性休克过敏，这主要是由于其巨噬细胞功能障碍。响应 LPS，AhR KO 小鼠的骨髓源性巨噬细胞 (BMDM) 分泌大量白细胞介素 1 β (IL-1 β)。由于通过用表达 Pai-2 的腺病毒转导补充纤溶酶原激活剂抑制剂 2 (Pai-2) 表达来抑制增强的 IL-1 β 分泌，因此减少的 Pai-2 表达可能是 AhR KO 小鼠 BMDM 增加 IL-1 β 分泌的原因。基因表达分析表明，AhR 通过涉及 NF-kappa B 而不是 AhR 核转位子 (Arnt) 的机制，以 LPS 依赖性方式直接调节 Pai-2 的表达。加上AhR配体3-甲基胆蒽部分保护野生型AhR小鼠免受内毒素诱导的死亡的结果，这些结果提出了适当的AhR配体可用于治疗炎症性疾病患者的可能性。
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-1 beta (IL-1 beta). Since the enhanced IL-1 beta 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-1 beta 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-kappa B 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.