ArticleActa pharmacologica Sinica2022
TNF-α impairs EP4 signaling through the association of TRAF2-GRK2 in primary fibroblast-like synoviocytes.
Article in Acta pharmacologica Sinica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 28 citations in OpenAlex.
- Recent advances in the development of GRK2 inhibitors: blocking the interaction of GRK2 with its partners.Acta pharmacologica Sinica · 2026Review
- Asparagus Polysaccharide Ameliorates TNF-α-Mediated MH7A Cell Dysfunction and Collagen-Induced Arthritis in Mice.Cell biochemistry and biophysics · 2026Article
- PGE2-mediated NK cell reprogramming drives acquired immunotherapy resistance in lung adenocarcinoma.Journal for immunotherapy of cancer · 2026Article
- Paroxetine as a Therapeutic Agent in Inflammatory Osteolysis: Mechanistic Insights and Efficacy.Drug design, development and therapy · 2026Article
- The intersection of GRK2 and PGE2 in rheumatoid arthritis: a comprehensive update on pathophysiology and treatment.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- GRK2 activates TRAF2-NF-Acta pharmaceutica Sinica. B · 2025Article
- Inhibition of GRK2-PDE4D Axis Suppresses Fibroblast-Like Synoviocytes Hyperplasia and Alleviates Experimental Arthritis.International journal of biological sciences · 2025Article
- Unveiling the Role of GRK2: From Immune Regulation to Cancer Therapeutics.Mediators of inflammation · 2025Review
- TRAF2 regulates the progression of pulmonary fibrosis through β-catenin-Snail signaling pathway.Frontiers in public health · 2025Article
- Quantitative proteomic analysis of circulating exosomes reveals the mechanism by which Triptolide protects against collagen-induced arthritis.Immunity, inflammation and disease · 2024Article
- CP-25 inhibits the hyperactivation of rheumatic synoviocytes by suppressing the switch in GCell communication and signaling : CCS · 2023Article
- Paroxetine Attenuates Chondrocyte Pyroptosis and Inhibits Osteoclast Formation by Inhibiting NF-κB Pathway Activation to Delay Osteoarthritis Progression.Drug design, development and therapy · 2023Article
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Authors and funding
12 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Our previous study showed that chronic treatment with tumor necrosis factor-α (TNF-α) decreased cAMP concentration in fibroblast-like synoviocytes (FLSs) of collagen-induced arthritis (CIA) rats. In this study we investigated how TNF-α impairs cAMP homeostasis, particularly clarifying the potential downstream molecules of TNF-α and prostaglandin receptor 4 (EP4) signaling that would interact with each other. Using a cAMP FRET biosensor PM-ICUE3, we demonstrated that TNF-α (20 ng/mL) blocked ONO-4819-triggered EP4 signaling, but not Butaprost-triggered EP2 signaling in normal rat FLSs. We showed that TNF-α (0.02-20 ng/mL) dose-dependently reduced EP4 membrane distribution in normal rat FLS. TNF-α significantly increased TNF receptor 2 (TNFR2) expression and stimulated proliferation in human FLS (hFLS) via ecruiting TNF receptor-associated factor 2 (TRAF2) to cell membrane. More interestingly, we revealed that TRAF2 interacted with G protein-coupled receptor kinase (GRK2) in the cytoplasm of primary hFLS and helped to bring GRK2 to cell membrane in response of TNF-α stimulation, the complex of TRAF2 and GRK2 then separated on the membrane, and translocated GRK2 induced the desensitization and internalization of EP4, leading to reduced production of intracellular cAMP. Silencing of TRAF2 by siRNA substantially diminished TRAF2-GRK2 interaction, blocked the translocation of GRK2, and resulted in upregulated expression of membrane EP4 and intracellular cAMP. In CIA rats, administration of paroxetine to inhibit GRK2 effectively improved the symptoms and clinic parameters with significantly reduced joint synovium inflammation and bone destruction. These results elucidate a novel form of cross-talk between TNFR (a cytokine receptor) and EP4 (a typical G protein-coupled receptor) signaling pathways. The interaction between TRAF2 and GRK2 may become a potential new drug target for the treatment of inflammatory diseases.
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