Diosgenin, an Activator of 1,25D3-MARRS Receptor/ERp57, Attenuates the Effects of TNF-α by Causing ADAM10-Dependent Ectodomain Shedding of TNF Receptor 1

Yang, Won Seok; Moon, Soo Young; Lee, Mee Jeong; Lee, Eun Kyoung; Park, Su-Kil

doi:10.1159/000484396

Cited by 19 publications

(8 citation statements)

References 34 publications

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“…We showed that overexpression of LRG1 in HUVECs resulted in the shedding of the TNFR1 ectodomain into conditioned medium, suggesting that the inhibitory effect of LRG1 on TNF-α-induced EC activation is mediated by post-translational modification of TNFR1. Structural analysis of the LRG1 protein sequence revealed an absence of known protease domains, but we showed that LRG1 increased the level of the active form of ADAM10, a sheddase with the known role of releasing soluble TNFR1 ectodomain in other contexts (Yang et al, 2015(Yang et al, , 2017. Consistent with this observation, the effect of LRG1 on TNFR1 shedding in HUVECs was partially abrogated in the presence of an ADAM10 inhibitor.…”

Section: Discussionsupporting

confidence: 78%

Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor

Pang

Ghim

Liu

et al. 2021

Front. Cell Dev. Biol.

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Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1–/– mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1–/–mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.

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Section: Discussionsupporting

confidence: 78%

Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor

Pang

Ghim

Liu

et al. 2021

Front. Cell Dev. Biol.

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“…Relt expression begins in pre-ameloblasts, continues through the secretory stage and, like Adam10 , abruptly ends as the ameloblasts enter the transition stage. Since ADAM10 is a sheddase that can cleave specific TNFRSF members and release them from the cell membrane 18,19 , we asked if ADAM10 can cleave RELT within its extracellular domain. To demonstrate rhADAM10 was proteolytically active, we incubated ADAM10 with its known substrate N-cadherin.…”

Section: Resultsmentioning

confidence: 99%

ADAM10 is Expressed by Ameloblasts, Cleaves the RELT TNF Receptor Extracellular Domain and Facilitates Enamel Development

Ikeda

Shahid

Blumberg

et al. 2019

Sci Rep

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MMP20 cleaves cadherins and may facilitate cell movement, however MMP20 is not known to cleave tight junction or desmosome proteins. Ameloblasts had not previously been screened for membrane anchored proteases that could contribute to cell movement. Here we performed a PCR screen for proteolyticlly active A Disintegrin And Metalloproteinase (ADAM) family members. These proteinases are termed sheddases because they have a transmembrane domain and their catalytic domain on the cell surface can function to release anchored proteins. Significantly, ADAMs can be targeted to specific substrates on the cell membrane through their interaction with tetraspanins. Six ADAMs (ADAM8, 9, 10, 15, 17, 19) were expressed in mouse enamel organs. We show that Adam10 expression begins in the apical loop, continues through the secretory stage and abruptly ends at the transition stage when ameloblast migration ceases. ADAM10 cleaves cadherins and tight junction plus desmosome proteins and is well characterized for its role in cell movement. ADAM10 facilitated LS8 cell migration/invasion through a Matrigel coated membrane and we demonstrate that ADAM10, but not ADAM17 cleaves the RELT extracellular domain. This striking result is significant because RELT mutations cause amelogenesis imperfecta (AI) and this directly links ADAM10 to an important role in enamel development.

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“…Serum proinflammatory factors were significantly elevated after reperfusion and diosgenin demonstrated anti-inflammatory properties [ 22 ], resulting in a decrease in the level of serum inflammatory markers TNF-α and IL-1β ( Figure 4A, 4B ). Lysosomal enzyme MPO is involved in diseases such as inflammation, vasculitis, and atherosclerosis [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Diosgenin Protects Rats from Myocardial Inflammatory Injury Induced by Ischemia-Reperfusion

et al. 2018

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BackgroundDiosgenin, a phytosteroid sapogenin, has anti-inflammatory properties shown to reduce myocardial ischemia-reperfusion injury (MIRI). However, the specific mechanism by which this is achieved is not clear. This study investigated the protective effects of diosgenin on myocardial ischemia/reperfusion (I/R) and the potential anti-inflammatory mechanisms.Material/MethodsHealthy adult male SD rats, body weight (b.w.) 250–280 g, were used to model ischemia-reperfusion injury (IRI) and were administered diosgenin (50 mg/kg and 100 mg/kg b.w.) intragastrically for 4 consecutive weeks before surgery. The left anterior descending artery (LAD) was ligated to induce myocardial ischemia for 30 min and reperfusion for 30 min, 60 min, and 120 min while relevant indicators were detected.ResultsBoth 50 mg and 100 mg diosgenin oral administration increased left ventricular developed pressure (LVDP) and maximum changing rate of ventricular pressure (±dp/dtmax), decreased left ventricular end-diastolic pressure (LVEDP), and myocardial enzyme markers. TTC staining suggested that diosgenin reduced myocardial infarct size in the rat model. Pathological results showed that myocardial ischemia and inflammation were alleviated by diosgenin. In addition, the increased expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) in serum, and myeloperoxidase (MPO) in myocardium were significantly suppressed by diosgenin administration. Diosgenin further inhibited the phosphorylation of transcription factor NF-κB and modulated the expression of downstream inflammatory cytokines by regulating the activation of p38-MAPK and JNK pathways.ConclusionsResults demonstrate diosgenin plays an anti-inflammatory role in the protection of MIRI through regulation of p38-MAPK and JNK pathways and phosphorylation of NF-κB.

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Diosgenin, an Activator of 1,25D3-MARRS Receptor/ERp57, Attenuates the Effects of TNF-α by Causing ADAM10-Dependent Ectodomain Shedding of TNF Receptor 1

Cited by 19 publications

References 34 publications

Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor

Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor

ADAM10 is Expressed by Ameloblasts, Cleaves the RELT TNF Receptor Extracellular Domain and Facilitates Enamel Development

Diosgenin Protects Rats from Myocardial Inflammatory Injury Induced by Ischemia-Reperfusion

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