β-Arrestin 2 Negatively Regulates Toll-like Receptor 4 (TLR4)-triggered Inflammatory Signaling via Targeting p38 MAPK and Interleukin 10
β-Arrestin 2 Negatively Regulates Toll-like Receptor 4 (TLR4)-triggered Inflammatory Signaling via Targeting p38 MAPK and Interleukin 10
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DOI：
10.1074/jbc.m114.591495
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发表时间：
2014-08-15
影响因子：
4.8
通讯作者：
Yin, Deling
中科院分区：
文献类型：
--
作者：
Li, Hui;Hu, Dan;Yin, Deling
Toll样受体（TLR）信号中IL-10产生的控制仍有待阐明。在这里，我们报告说，β-arrestin 2积极调节TLR触发的IL-10的生产在p38丝裂原活化蛋白激酶（MAPK）依赖的机制。对包括腹膜巨噬细胞和HEK 293/TLR 4细胞在内的细胞的体外研究已经证明，β-抑制蛋白2与p38形成复合物，并在脂多糖（LPS）刺激后促进p38活化。β-arrestin 2的缺乏和p38 MAPK活性的抑制均改善TLR 4刺激的IL-10应答。此外，体内实验表明，缺乏β-抑制蛋白2的小鼠产生更少量的IL-10，并且更容易受到LPS诱导的脓毒性休克的影响，这通过阻断IL-10信号而进一步增强。这些结果揭示了β-arrestin 2负调节TLR 4介导的炎症反应的新机制。
The control of IL-10 production in Toll-like receptor (TLR) signals remains to be elucidated. Here, we report that beta-arrestin 2 positively regulates TLR-triggered IL-10 production in a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism. In vitro studies with cells including peritoneal macrophages and HEK293/TLR4 cells have demonstrated that beta-arrestin 2 forms complexes with p38 and facilitates p38 activation after lipopolysaccharide (LPS) stimulation. Deficiency of beta-arrestin 2 and inhibition of p38 MAPK activity both ameliorate TLR4-stimulated IL-10 response. Additionally, in vivo experiments show that mice lacking beta-arrestin 2 produce less amount of IL-10, and are more susceptible to LPS-induced septic shock which is further enhanced by blocking IL-10 signal. These results reveal a novel mechanism by which beta-arrestin 2 negatively regulates TLR4-mediated inflammatory reactions.