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Title 

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

Authors 

M HayashiMun Chual RhoA FukamiA EnomotoS NonakaY SekiguchiT YanagisawaA YamashitaT NogawaY KamanoK Komiyama

Publisher 

American Society for Pharmacology and Experimental Therapeutics (ASPET)

Issue Date 

2002

Citation 

Journal of Pharmacology and Experimental Therapeutics, vol. 303, no. 1, pp. 104-109

Keywords 

20,21 epoxyresibufogenin 3 formatebufadienolidecalcitriolCD23 antigeninterleukin 11interleukin 2interleukin 3interleukin 4interleukin 6interleukin 6 receptor

Abstract 

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 pA2 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)α-induced growth suppression in TNFα-sensitive L929 cells. ERBF also did not affect IL-4-stimulated expression of FcεR 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 1α,25-dihydroxyvitamin D3. 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.

ISSN 

0022-3565

Link 

http://dx.doi.org/10.1124/jpet.102.036137

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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