Cardiac glycosides inhibit TNF-alpha/NF-kappaB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor.
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.
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.
Qingfeng
Q
Yang
Wei
W
Huang
Catherine
C
Jozwik
Yong
Y
Lin
Mirta
M
Glasman
Hung
H
Caohuy
Meera
M
Srivastava
Dominic
D
Esposito
William
W
Gillette
James
J
Hartley
Harvey B
HB
Pollard
D015153:Blotting, Western; D004074:Digitoxin / Q000494:pharmacology*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D004074:Digitoxin; D008156:Luciferases