Bachmaier Kurt, Toya Sophie, Gao Xiaopei, Triantafillou Thomas, Garrean Sean, Park Gye Young, Frey Randall S, Vogel Stephen, Minshall Richard, Christman John W, Tiruppathi Chinnaswamy, Malik Asrar B
Department of Pharmacology, College of Medicine, University of Illinois, E403, Medical Science Building, M/C 868, 835 S. Wolcott Avenue, Chicago, Illinois 60612, USA.
Nat Med. 2007 Aug;13(8):920-6. doi: 10.1038/nm1607. Epub 2007 Jul 8.
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-kappaB (NF-kappaB) 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.
E3泛素连接酶Cblb在预防慢性炎症和自身免疫方面发挥着关键作用。在此我们表明，Cblb在急性肺部炎症中也具有意想不到的功能。给予脂多糖（LPS）后，Cblb可减轻肺部炎症细胞的滞留。在急性肺部炎症依赖LPS受体（Toll样受体4，TLR - 4）的多微生物败血症模型中，Cblb表达缺失会加剧急性肺部炎症并降低生存率。Cblb缺失会显著增加败血症诱导的炎性细胞因子和趋化因子的释放。Cblb控制TLR4与细胞内衔接蛋白MyD88之间的关联。野生型Cblb的表达，而非缺乏E3泛素连接酶功能的Cblb突变体的表达，可阻止在用LPS刺激的单核细胞中转录因子核因子-κB（NF-κB）报告基因的活性。在缺乏Cblb的情况下，中性粒细胞细胞表面TLR4表达的下调受损。我们的数据表明，Cblb调节由败血症诱导的TLR4介导的急性炎症反应。
