TNF-α impairs EP4 signaling through the association of TRAF2-GRK2 in primary fibroblast-like synoviocytes

Tai, Yu Tzu; Huang, Bei; Guo, Pengfei; Wang, Zhen; Zhou, Zhengwei; Wang, Manman; Sun, Hairui; Hu, Yong; Xu, Shenglin; Zhang, Lingling; Wang, Qingtong; Wei, Wei

doi:10.1038/s41401-021-00654-z

Cited by 10 publications

(5 citation statements)

References 65 publications

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“…Crosstalk between cytokine and chemokine signaling contributes to RA progression by activating FLS (Muntyanu et al, 2016). The proinflammatory cytokines TNF-α and IL-6 are known to be involved in this process (Tai et al, 2021); therapeutic strategies that restore their levels could prevent RA development. TNF-α is present at a high concentration in the serum and synovial fluid of RA patients, and exposure of FLS from these patient to high levels of TNF-α decreased total histone levels and increased acetylation of the remaining histones through recruitment of nuclear factor (NF)-κB p65 (Sohn et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Wang

Yan

et al. 2021

Front. Pharmacol.

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Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and subsequent destruction of adjacent articular cartilage and bone. In our previous work we showed that phosphatase and tension homolog deleted on chromosome 10 (PTEN) contributes to the activation of fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA), but the underlying mechanism is not unknown. In this study, we show that PTEN is downregulated while DNA methyltransferase (DNMT)1 is upregulated in FLS from RA patients and a rat model of AIA. DNA methylation of PTEN was increased by administration of tumor necrosis factor (TNF)-α in FLS of RA patients, as determined by chromatin immunoprecipitation and methylation-specific PCR. Treatment with the methylation inhibitor 5-azacytidine suppressed cytokine and chemokine release and FLS activation in vitro and alleviated paw swelling in vivo. PTEN overexpression reduced inflammation and activation of FLS via protein kinase B (AKT) signaling in RA, and intra-articular injection of PTEN-expressing adenovirus into the knee of AIA rats markedly reduced inflammation and paw swelling. Thus, PTEN methylation promotes the inflammation and activation of FLS in the pathogenesis of RA. These findings provide insight into the molecular basis of articular cartilage destruction in RA, and indicate that therapeutic strategies that prevent PTEN methylation may an effective treatment.

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Section: Introductionmentioning

confidence: 99%

PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Wang

Yan

et al. 2021

Front. Pharmacol.

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“…Arthritis score was determined by the grade of 0−4: 0, no joint swelling; 1, mild swelling of the little toe joints; 2, moderate swelling of the toe joints and ankle; 3, obvious swelling of the paw; 4, severe swelling involving entire paw, including the ankle. The arthritis index is the cumulative score for all four paws 15 …”

Section: Methodsmentioning

confidence: 99%

Quantitative proteomic analysis of circulating exosomes reveals the mechanism by which Triptolide protects against collagen‐induced arthritis

Liu,

Wang

et al. 2024

Immunity Inflam & Disease

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IntroductionTriptolide (TP), a natural product derived from the herbal medicine Tripterygium wilfordii, exhibits potent immunosuppressive activity. However, the mechanisms underlying its effects in rheumatoid arthritis remain incompletely understood.MethodsCollagen‐induced arthritis (CIA) model was induced in Sprague−Dawley rats by immunization with bovine type II collagen, and TP was administrated as treatment. The therapeutic effect of TP was evaluated based on paw swelling, histopathology, and serum levels of inflammatory factors. Exosomes isolated from rat serum were characterized by transmission electron microscopy, dynamic light scattering, and western blot analysis. Proteomic profiling of exosomes was analyzed by direct DIA quantitative proteomics analysis. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes databases were employed for enrichment analysis related to molecular function, biological processes, and signaling pathways. Western blot analysis was used to analyze differentially expressed proteins.ResultsTP treatment ameliorated arthritic phenotypes in CIA rats as evidenced by reduced arthritis score, paw swelling, pathological injury severity scores, and serum levels of inflammatory cytokines. The proteomic analysis revealed that TP treatment significantly inhibited complement and coagulation cascades, interleukin‐17 signaling pathway, and cholesterol metabolism, which were reactivated in CIA rats. Importantly, lipocalin 2 (LCN2) and myeloperoxidase (MPO) levels were markedly upregulated in the CIA group but suppressed upon TP administration. Furthermore, in synovial tissues, LCN2 and MPO expression levels were also elevated in the CIA group but decreased following TP treatment.ConclusionOur findings demonstrate that TP alleviates CIA, possibly through modulation of exosomal LCN2 and MPO proteins.

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“…TNF-α is the primary mediator of inflammatory reaction and plays a crucial role in the progression of RA. The excessive TNF-α could destroy cAMP homeostasis and decrease the cAMP level of FLSs in collagen-induced arthritis rats [26]. In addition, some researchers have proposed that the increased level of cAMP could significantly suppress the production of TNF-α [27].…”

Section: Kegg Pathway Enrichment Analysismentioning

confidence: 99%

Uncovering the effective substances and mechanism of Ipomoea pes‐caprae against rheumatoid arthritis using liquid chromatography‐mass spectrometry and targeted network pharmacology

Cheng

Cui

Hou

et al. 2023

J of Separation Science

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Ipomoea pes-caprae (L.) R. Br (Convolvulaceae) is a commonly used marine traditional Chinese medicine in the southern coastal areas of China. It has been widely used to treat rheumatoid arthritis, but its effective substances and antirheumatoid arthritis mechanism remain ambiguous. Hence, in this study, the chemical profile and absorbed ingredients of Ipomoea pes-caprae were elucidated by ultra-performance liquid chromatography-mass spectrometry. Moreover, targeted network pharmacology was used to clarify the mechanism of action of Ipomoea pes-caprae in treating rheumatoid arthritis. Finally, 23 compounds were identified in the aqueous extracts of Ipomoea pes-caprae and 12 absorbed ingredients were detected in rats' plasma. These 12 absorbed ingredients might be the essential effective substances of Ipomoea pes-caprae. The tissue distributions of 3 absorbed ingredients in rats were successfully analyzed. The targeted network pharmacological analysis results indicated that the regulation of inflammatory reaction, immune response, cell proliferation, and apoptosis were the critical mechanism of Ipomoea pes-caprae against rheumatoid arthritis. This study successfully clarified the effective substances and potential mechanisms of Ipomoea pes-caprae in treating rheumatoid arthritis. The results of this research could provide a valuable reference for further scientific research and clinical application.Article Related Abbreviations: AIA, adjuvant-induced arthritis; CFA, complete Freund's adjuvant; CYP450, cytochrome P450; FLSs, fibroblast-like synoviocytes; KEGG, Kyoto Encyclopedia of Genes and Genomes; RA, rheumatoid arthritis; TNF, tumor necrosis factor; UPLC Q-TOF-MS, ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry; UPLC-TQ-MS, ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry.

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TNF-α impairs EP4 signaling through the association of TRAF2-GRK2 in primary fibroblast-like synoviocytes

Cited by 10 publications

References 65 publications

PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Quantitative proteomic analysis of circulating exosomes reveals the mechanism by which Triptolide protects against collagen‐induced arthritis

Uncovering the effective substances and mechanism of Ipomoea pes‐caprae against rheumatoid arthritis using liquid chromatography‐mass spectrometry and targeted network pharmacology

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