E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury
E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury
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DOI：
10.1038/nm1607
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发表时间：
2007-08-01
期刊：
影响因子：
82.9
通讯作者：
Malik, Asrar B.
中科院分区：
文献类型：
--
作者：
Bachmaier, Kurt;Toya, Sophie;Malik, Asrar B.
E3泛素连接酶Cblb在预防慢性炎症和自身免疫中起着关键作用。在这里，我们展示了Cblb在急性肺部炎症中也有意想不到的作用。CBLB可减轻脂多糖(LPS)注射后炎性细胞在肺部的滞留。在多菌败血症模型中，急性肺部炎症依赖于脂多糖受体(Toll样受体4，TLR-4)，Cblb表达的缺失加剧了急性肺部炎症，降低了存活率。Cblb的缺失显著增加了脓毒症引起的炎性细胞因子和趋化因子的释放。CBLB控制TLR4和细胞内适配器MyD88之间的关联。野生型Cblb的表达，而不是缺乏E3泛素连接酶功能的Cblb突变体的表达，阻止了转录因子核因子-kappa B(NF-kappa B)的报告基因在受到内毒素攻击的单核细胞中的活性。中性粒细胞表面TLR4表达的下调在缺乏Cblb的情况下受到损害。我们的数据显示，Cblb调节TLR4介导的脓毒症诱导的急性炎症反应。
The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappa B (NF-kappa B) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.