Diosgenin, an Activator of 1,25D 3 -MARRS Receptor/ERp57, Attenuates the Effects of TNF-α by Causing ADAM10-Dependent Ectodomain Shedding of TNF Receptor 1

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Abstract

Background/Aims: We investigated how diosgenin, a steroidal sapogenin, has anti-tumor necrosis factor-α (TNF-α) effects in human aortic endothelial cells (HAECs). Methods: Tumor necrosis factor receptor 1 (TNFR1) was assessed by Western blot analysis. Intracellular Ca 2+ was measured using Fluo-4 AM. Immunofluorescence staining was performed for a disintegrin and metalloprotease 10 (ADAM10). Results: Diosgenin (1 ∼ 100 nM) induced ectodomain shedding of TNFR1 within 30 min and attenuated TNF-α-induced intercellular adhesion molecule-1 (ICAM-1) expression. Upon treatment with diosgenin, extracellular Ca 2+ entered into the cells via L-type calcium channels, whereas diosgenin-induced ectodomain shedding of TNFR1 was almost completely inhibited by BAPTA-AM (intracellular Ca 2+ chelator), verapamil (L-type calcium channel antagonist) and the absence of extracellular Ca 2+ . Diosgenin caused translocation of ADAM10 to the cell surface, which was mediated by extracellular Ca 2+ influx. Depletion of ADAM10 prevented diosgenin-induced ectodomain shedding of TNFR1 and abolished the inhibitory effect of diosgenin on TNF-α-induced ICAM-1 expression. Diosgenin did not induce extracellular Ca 2+ influx and ectodomain shedding of TNFR1 in cells depleted of 1,25D 3 -membrane associated rapid response steroid-binding receptor (1,25D 3 -MARRS receptor/ERp57). Conclusion: Diosgenin elicits L-type calcium channel-mediated extracellular Ca 2+ influx, and thereby induces ADAM10-mediated ectodomain shedding of TNFR1. This effect of diosgenin was exerted through 1,25D 3 -MARRS receptor/ERp57.

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Yang, W. S., Moon, S. Y., Lee, M. J., Lee, E. K., & Park, S. K. (2017). Diosgenin, an Activator of 1,25D 3 -MARRS Receptor/ERp57, Attenuates the Effects of TNF-α by Causing ADAM10-Dependent Ectodomain Shedding of TNF Receptor 1. Cellular Physiology and Biochemistry, 43(6), 2434–2445. https://doi.org/10.1159/000484396

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