Cardiac glycosides inhibit TNF-α/NF-κB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor
Proceedings of the National Academy of Sciences2005Vol. 102(27), pp. 9631–9636
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Qingfeng Yang, Wei Huang, Catherine Jozwik, Yong Lin, Mirta Glasman, H. Caohuy, Meera Srivastava, Dominic Esposito, William Gillette, James L. Hartley, Harvey B. Pollard
Abstract
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.
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