nature20121213-6

来自美国盐湖城犹他大学的科学家研究发现IL-1β可破坏上皮稳定性和血管渗透性,并发现这是不依赖于核转录因子NF-κB的激活的,抑制参与这一通路的蛋白具有改善炎症疾病动物模型的结果。

-2012年12月13日《自然》


中文翻译


【题目】白介素受体激活MYD88–ARNO–ARF6级联反应以干扰血管稳定性

【译文】固有免疫反应对于抵御感染性疾病至关重要。巨噬细胞和其他细胞通过释放细胞因子,如白介素-1β (IL-1β),对感染产生应答。白介素1β (IL-1β)反过来可以激活髓样分化因子88(MYD88)介导的可以引起炎症细胞激活和募集的核转录因子κB (NF-κB)依赖的转录通路。 上皮细胞通常作为炎症细胞移除血液、移入组织的屏障,它们也是炎症反应的重要调控因子。矛盾的是,对于成功免疫防御重要的细胞因子也对上皮细胞-细胞相互作用具有干扰作用,并可以触发屏障功能降低和组织结构分离。这种屏障分离的机制及其与常规NF-κB通路的关系还不十分清楚。本研究表明人体外细胞模型中IL-1β对上皮稳定性的直接、立即及破坏性作用是NF-κB非依赖的,而不是通过小GTP酶ADP核糖基化因子6 (ARF6)及其激动因子ARF核结合位点启动子(ARNO,又称CYTH2)产生的信号结果。此外,本研究表明ARNO直接与衔接蛋白MYD88结合,因此我们提出MYD88–ARNO–ARF6通路邻近IL-1β信号通路,而不同于NF-κB介导的通路。最后,研究表明ARF鸟嘌呤核苷酸交换因子(如ARNO)的抑制剂SecinH3可以增强血管稳定性,并显著改善炎性关节炎和急性炎症动物模型的结果。

英文原稿


[Title]: Interleukin receptor activates a MYD88–ARNO–ARF6 cascade to disrupt vascular stability

[Authors]:Weiquan Zhu,1, 2, 11 Nyall R. London,1, 2, 3, 11 Christopher C. Gibson,2, 4, 11 Chadwick T. Davis,2, 5 Zongzhong Tong,6 Lise K. Sorensen,2 Dallas S. Shi,2, 5 Jinping Guo,1, 2, 7 Matthew C. P. Smith,1, 2, 3 Allie H. Grossmann,2, 8 Kirk R. Thomas1, 2 & Dean Y. Li1, 2, 3, 9, 10

[Abstract]The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-dependent transcriptional pathway that results in inflammatory-cell activation and recruitment. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response. Paradoxically, the cytokines vital to a successful immune defence also have disruptive effects on endothelial cell–cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1β on endothelial stability in a human in vitro cell model are NF-κB independent and are instead the result of signalling through the small GTPase ADP-ribosylation factor 6 (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as CYTH2). Moreover, we show thatARNO binds directly to the adaptor protein MYD88, and thus propose MYD88–ARNO–ARF6 as a proximal IL-1β signalling pathway distinct from that mediated by NF-κB. Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors such asARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.

原文地址

http://www.nature.com/nature/journal/v492/n7428/full/nature11603.html

本站声明: 生物文库所有文章欢迎转载,所有文章未说明,均属于原创,转载均请注明出处。
本文链接: http://www.bioku.cn/201301/nature-interleukin-receptor-myd88-arno-arf6-cascade-vascular/
版权所有: 生物文库 - 生物医学、生物技术核心期刊文摘

留言


5 − 四 =


沪ICP备12028140号
点击这里给我发消息   点击这里给我发消息