Yang Qingfeng, Huang Wei, Jozwik Catherine, Lin Yong, Glasman Mirta, Caohuy Hung, Srivastava Meera, Esposito Dominic, Gillette William, Hartley James, Pollard Harvey B
Department of Anatomy, Physiology, and Genetics and Institute for Molecular Medicine, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9631-6. doi: 10.1073/pnas.0504097102. Epub 2005 Jun 27.
Digitoxin and structurally related cardiac glycoside drugs potently block activation of the TNF-alpha/NF-kappaB signaling pathway. We have hypothesized that the mechanism might be discovered by searching systematically for selective inhibitory action through the entire pathway. We report that the common action of these drugs is to block the TNF-alpha-dependent binding of TNF receptor 1 to TNF receptor-associated death domain. This drug action can be observed with native cells, such as HeLa, and reconstituted systems prepared in HEK293 cells. All other antiinflammatory effects of digitoxin on NF-kappaB and c-Jun N-terminal kinase pathways appear to follow from the blockade of this initial upstream signaling event.
洋地黄毒苷及结构相关的强心苷类药物可有效阻断肿瘤坏死因子-α/核因子-κB信号通路的激活。我们推测,通过系统地在整个信号通路中寻找选择性抑制作用,或许能够发现其作用机制。我们报告称,这些药物的共同作用是阻断肿瘤坏死因子-α依赖的肿瘤坏死因子受体1与肿瘤坏死因子受体相关死亡结构域的结合。这种药物作用在天然细胞(如HeLa细胞)以及在人胚肾293细胞中构建的重组系统中均能观察到。洋地黄毒苷对核因子-κB和c-Jun氨基末端激酶信号通路的所有其他抗炎作用似乎都源于对这一初始上游信号事件的阻断。