Paeoniflorin-6′-o-benzene sulfonate ameliorates the progression of adjuvant-induced arthritis by inhibiting the interaction between Ahr and GRK2 of fibroblast-like synoviocytes

Zhang, Bin-Jie; Wang, Yueye; Jia, Chengyan; Li, Susu; Wang, Xinwei; Xu, Yuan; Chen, A-Yuan; Xu, He-Peng; Wang, Chun; Yang, Zhaoyi; Wei, Wei; Cao, Yan

doi:10.1016/j.intimp.2022.108678

Cited by 2 publications

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“…In addition, CP-25 inhibits the progress of AA rats by reducing inflammation, immunity and joint injury (16). All of the previous studies by our group proved that CP-25 may be an effective drug for RA (5)(6)(7)(8)(9)(10)(11)15,16). In the present study, the effect of CP-25 on the interaction between GRK2 and Gβγ was evaluated.…”

Section: Discussionmentioning

confidence: 82%

“…Paeoniflorin-6'O-benzene sulfonate (CP-25; patent number in China: ZL201210030616.4) is a structurally modified compound from paeoniflorin with anti-inflammatory and immunomodulatory effects in RA animal models and other immune diseases (7)(8)(9)(10). It was found that CP-25 ameliorated FLS abnormal proliferation and migration by inhibiting GRK2 translocation (11) and re-sensitizing EP4 (6), which was an important mechanism of CP-25 in improving FLS dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Paeoniflorin‑6'O‑benzene sulfonate suppresses ﬁbroblast‑like synoviocytes proliferation and migration in rheumatoid arthritis through regulating GRK2‑Gβγ interaction

et al. 2022

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Rheumatoid arthritis (RA) is a chronic autoimmune disease. Enhanced G protein coupled receptor kinase 2 (GRK2) translocation and prostaglandin E4 receptor (EP4) desensitization play a critical role in fibroblast-like synoviocytes (FLS) dysfunction. Paeoniflorin-6'O-benzene sulfonate (CP-25) exerts a protective effect in arthritis in the RA animal models. To demonstrate the role of Gβγ in EP4 desensitization and the mechanisms of CP-25 that protects FLS in RA, RA-FLS and adjuvant-induced arthritis (AA-FLS) were isolated from synovium of RA patients and AA rats. RA-FLS, AA-FLS and MH7A were treated with CP-25, Gβγ agonist and antagonist. The cell membrane expression of EP4, GRK2, and Gβγ were detected using western blot analysis. Co-immunoprecipitation (Co-IP) and immunofluorescence were adopted to detect the interactions of GRK2-Gβγ, GRK2-EP4, and EP4-Gβγ. Cell Counting Kit-8 and Transwell assay were used to analyze the proliferation and migration of the FLS. An increased membrane expression of GRK2 and Gβγ, enhanced GRK2-Gβγ interaction and decreased EP4 membrane expression in the RA synovial tissue were identified. In vitro, prostaglandin E2 (PGE 2 ) enhanced the proliferation and migration of FLS. CP-25 exhibited an inhibition effect similar to Gβγ inhibitor, which downregulated GRK2-EP4 interaction, blocked the translocation of GRK2, and reversed EP4 desensitization, leading to the suppression of the proliferation and migration induced by PGE 2 . These results elucidated that an enhanced GRK2-Gβγ interaction was involved in the EP4 desensitization and dysfunction. CP-25 regulated EP4-GRK2-Gβγ signaling and re-sensitized EP4 by inhibiting GRK2-Gβγ interaction. The regulation of EP4-Gβγ-GRK2 signaling may be a novel potential therapeutic target in RA.

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