Celastrol Inhibits Lipopolysaccharide-Stimulated Rheumatoid Fibroblast-Like Synoviocyte Invasion through Suppression of TLR4/NF-κB-Mediated Matrix Metalloproteinase-9 Expression

Li, Guoqing; Liú, Dan; Zhang, Yu; Qian, Yayun; Zhang, Hua; Guo, Shiyu; Sunagawa, Makoto; Hisamitsu, Tadashi; Liu, Yanqing

doi:10.1371/journal.pone.0068905

Cited by 75 publications

(64 citation statements)

References 35 publications

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“…We also noted that the number of the α-SMA + CMFs was reduced in the colonic mucosa of these knockout (KO) mice. This may be due to the reduced MyD88-dependent fibroblast migration and differentiation as has been noted in the small intestine and other organs (22, 53). However, the α–SMA + positive cells (a.k.a.…”

Section: Resultsmentioning

confidence: 90%

TLR4 Activation Enhances the PD-L1–Mediated Tolerogenic Capacity of Colonic CD90+ Stromal Cells

Beswick

Johnson

Saada

et al. 2014

The Journal of Immunology

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Signaling via Programmed Death Ligand (PD-L)-1 and PD-L2 is crucial for maintaining peripheral tolerance. CD90+ myofibroblasts/fibroblasts (CMFs) are major PD-1 ligands -expressing cells in normal human colonic mucosa. CMFs suppress activated CD4+ T cell proliferation via PD-1 ligands. It is not known whether signaling through TLRs contribute to the regulation PD-1 ligands on CMFs upon colonic mucosal tolerance. Herein, we demonstrated that stimulation of TLR4 on human CMFs upregulates PD-L1, but not PD-L2, and reinforces CMF-mediated suppression of CD4+ T cell proliferation and IFN-γ production. TLR4-mediated upregulation of PD-L1 on CMFs involved NF-κB pathways and was JAK2- and MyD88-dependent. MyD88-dependent stimulation of TLR1/2 and TLR 5 also upregulated PD-L1 expression on CMFs in culture. PD-L1 expression was drastically decreased in vivo in the colonic mucosa of mice devoid of MyD88. Induction of MyD88 deficiency in CMFs in fibroblast-specific MyD88 conditional knockout mice resulted in a strong increase in a mucosal IFN-γ expression concomitantly with the abrogation of PD-L1 expression in CMFs under homeostasis and epithelial injury induced by dextran sodium sulfate. Together these data suggest that MyD88-dependent TLR stimulation of CMFs in the normal colonic mucosa may reinforce these cells' anti-inflammatory capacity, and thus contribute to the maintenance of mucosal tolerance.

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Section: Resultsmentioning

confidence: 90%

TLR4 Activation Enhances the PD-L1–Mediated Tolerogenic Capacity of Colonic CD90+ Stromal Cells

Beswick

Johnson

Saada

et al. 2014

The Journal of Immunology

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“…It has been reported that the translocation and subsequent DNA binding of NF-κB in inflamed synovium transactivates [42,53] . Therefore, NF-κB has been extensively studied to determine its role in the pathogenesis of RA, and NF-κB inhibition has been explored as a therapeutic approach to the disease.…”

Section: Discussionmentioning

confidence: 99%

“…RA FLSs have the ability to secrete zinc-dependent proteases such as MMPs, which promote degradation of the extracellular matrix proteins in joints and bones [41] . MMP-9, also called collagenases, are induced in RA FLSs by pro-inflammatory cytokines and LPS [3,42] . A recent report suggests that MMP-9 plays an important role in RA FLS migration and invasion induced by LPS [42] .…”

Section: Effect Of Hyperoside On Lps-induced Production Of Pro-inflammentioning

confidence: 99%

“…MMP-9, also called collagenases, are induced in RA FLSs by pro-inflammatory cytokines and LPS [3,42] . A recent report suggests that MMP-9 plays an important role in RA FLS migration and invasion induced by LPS [42] . Because hyperoside inhibited RA FLS migration, we examined the effect of hyperoside on MMP-9 secretion in cultured media.…”

Section: Effect Of Hyperoside On Lps-induced Production Of Pro-inflammentioning

confidence: 99%

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Hyperoside exerts anti-inflammatory and anti-arthritic effects in LPS-stimulated human fibroblast-like synoviocytes in vitro and in mice with collagen-induced arthritis

Jin¹,

Yan

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: Hyperoside is a flavonol glycoside mainly found in plants of the genera Hypericum and Crataegus, which has shown anti-oxidant, anti-cancer and anti-inflammatory activities. In this study, we investigated the effects of hyperoside on human rheumatoid fibroblastlike synoviocytes (FLSs) in vitro and on mouse collagen-induced arthritis (CIA) in vivo. Methods: FLSs were isolated from primary synovial tissues obtained from rheumatoid arthritis (RA) patients and exposed to LPS (1 µg/mL). Cell viability and proliferation were measured with MTT and BrdU assay. Cell migration was assessed using wound-healing assay and Transwell assay. DNA binding of NF-κB was measured using a TransAM-NFkappaB kit. The localization of p65 subunit was detected with immunocytochemistry. CIA was induced in mice by primary immunization with Bovine Type II collagen (CII) emulsified in CFA, followed by a booster injection 3 weeks later. The arthritic mice were treated with hyperoside (25, 50 mg·kg -1 ·d -1, ip) for 3 weeks, and the joint tissues were harvested for histological analysis. Results: Hyperoside (10, 50, 100 µmol/L) dose-dependently inhibited LPS-induced proliferation and migration of human RA FLSs in vitro. Furthermore, hyperoside decreased LPS-stimulated production of TNF-α, IL-6, IL-1 and MMP-9 in the cells. Moreover, hyperoside inhibited LPS-induced phosphorylation of p65 and IκBα, and suppressed LPS-induced nuclear translocation of p65 and DNA biding of NF-κB in the cells. Three-week administration of hyperoside significantly decreased the clinical scores, and alleviated synovial hyperplasia, inflammatory cell infiltration and cartilage damage in mice with CIA. Conclusion: Hyperoside inhibits LPS-induced proliferation, migration and inflammatory responses in human RA FLSs in vitro by suppressing activation of the NF-κB signaling pathway, which contributes to the therapeutic effects observed in mice with CIA.

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“…Celastrus and various of its defined constituents possess anti-cancer, anti-inflammatory and anti-oxidant properties (1–8). Our previous studies demonstrated that the ethyl acetate extract of Celastrus orbiculatus (COE) has significant anti-tumor effects in vitro and in vivo (1,3,4,9–12). COE induced cytotoxicity and promoted the apoptosis of human hepatocellular carcinoma cells by inhibiting the Akt signaling pathway (9), and inhibited tumor angiogenesis by modulating the vascular endothelial growth factor signaling pathway (10).…”

Section: Introductionmentioning

confidence: 99%

Celastrus orbiculatus extract triggers apoptosis and autophagy via PI3K/Akt/mTOR inhibition in human colorectal cancer cells

et al. 2016

Self Cite

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Celastrus orbiculatus is used as a folk medicine in China for the treatment of numerous diseases. The ethyl acetate extract of Celastrus orbiculatus (COE) also displays a wide range of anti-cancer activities in the laboratory. However, the effectiveness of COE-induced autophagy and its mechanism of action in colorectal cancer cells have not been investigated thus far. The present study analyzed the effect of COE on HT-29 cell viability, apoptosis and autophagy using MTT assay, flow cytometry, transmission electron microscopy and western blotting. Additionally, the autophagy inhibitor 3-methyladenine and the autophagy inducer rapamycin were used to further explore the effects of COE-induced autophagy in HT-29 cells. The present study also examined whether the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling pathway was involved in the regulation of COE-induced autophagy. The results revealed that COE inhibited HT-29 cell proliferation and decreased cell survival in a time- and dose-dependent manner, and that COE possessed the ability to induce both apoptosis and autophagy in HT-29 cells. Furthermore, autophagy and apoptosis induced by COE synergized to inhibit colorectal cancer growth. In addition, COE treatment decreased the phosphorylation of Akt and its downstream effectors mTOR and p70S6K. Taken together, these results demonstrate that both autophagy and apoptosis were activated during COE treatment of HT-29 cells, and that COE-induced autophagy decreases the viability of HT-29 cells via a mechanism that may depend on the PI3K/Akt/mTOR/p70S6K signaling pathway. Furthermore, compounds that induce autophagy administered in combination with COE may be an attractive strategy for enhancing the anti-tumor potency of COE in colorectal cancer.

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Celastrol Inhibits Lipopolysaccharide-Stimulated Rheumatoid Fibroblast-Like Synoviocyte Invasion through Suppression of TLR4/NF-κB-Mediated Matrix Metalloproteinase-9 Expression

Cited by 75 publications

References 35 publications

TLR4 Activation Enhances the PD-L1–Mediated Tolerogenic Capacity of Colonic CD90+ Stromal Cells

TLR4 Activation Enhances the PD-L1–Mediated Tolerogenic Capacity of Colonic CD90+ Stromal Cells

Hyperoside exerts anti-inflammatory and anti-arthritic effects in LPS-stimulated human fibroblast-like synoviocytes in vitro and in mice with collagen-induced arthritis

Celastrus orbiculatus extract triggers apoptosis and autophagy via PI3K/Akt/mTOR inhibition in human colorectal cancer cells

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