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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Biological activity of a novel nonpeptide antagonist to the interleukin-6 receptor 20S,21-epoxy-resibufogenin-3-formate.

Interleukin (IL)-6 is a key mediator in the regulation and coordination of the immune response and participates in pathogenesis of cancer cachexia, autoimmune disease, and postmenopausal osteoporosis. In the course of a screening program aimed at IL-6 inhibitor from natural products, we isolated 20S,21-epoxy-resibufogenin-3-formate (ERBF) from bufadienolide and examined the effect of ERBF on activities of various cytokines. ERBF dose dependently suppressed IL-6 activity and caused a parallel rightward shift of dose-response curves to IL-6 at concentrations of 0.03 to 10 ng/ml. Analysis of data yields a pA(2) of 5.12 and a slope of 0.99. Selectivity of ERBF on activity of cytokines was examined using cytokine-dependent cell lines. ERBF did not affect IL-2-dependent growth of CTLL-2 cells, IL-3-dependent growth of Baf3 cells, or tumor necrosis factor (TNF)alpha-induced growth suppression in TNFalpha-sensitive L929 cells. ERBF also did not affect IL-4- stimulated expression of FcepsilonR II receptor ( CD23) in U-937 cells, the IL-8-induced chemotaxis of human neutrophils, or nerve growth factor-stimulated neuronal differentiation in PC-12 cells. In contrast, ERBF dose dependently suppressed IL-6-induced neuronal differentiation in PC-12 cells. Furthermore, ERBF suppressed only IL-6- induced osteoclast formation without affecting osteoclast formation induced by IL-11, leukemia inhibitory factor, and 1alpha,25-dihydroxyvitamin D(3). In receptor binding assay, unbound (free) IL-6 was increased in a dose-dependent manner by pretreatment with ERBF on IL-6 receptor ( IL-6R), suggesting that ERBF suppresses binding of IL-6 to IL-6R. These results clearly indicate that ERBF is a novel specific small molecule to show IL-6 receptor antagonist activity.[1]


  1. Biological activity of a novel nonpeptide antagonist to the interleukin-6 receptor 20S,21-epoxy-resibufogenin-3-formate. Hayashi, M., Rho, M.C., Fukami, A., Enomoto, A., Nonaka, S., Sekiguchi, Y., Yanagisawa, T., Yamashita, A., Nogawa, T., Kamano, Y., Komiyama, K. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
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