Regulatory effects of paeoniflorin-6′-O-benzene sulfonate (CP-25) on dendritic cells maturation and activation via PGE2-EP4 signaling in adjuvant-induced arthritic rats
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6′-O-benzene sulfonate (CP-25). PGE2 combined with tumor necrosis factor-α promoted DC maturation and activation through EP4-cAMP signaling. Treatment with CP-25 increased the endocytic capacity of DCs induced by PGE2. CP-25 inhibited the potency of DCs induced by the EP4 receptor agonist, CAY10598, to stimulate allogeneic T cells. Consistent with these findings, the CAY10598-induced upregulation of DC surface activation markers and production of IL-23 was significantly inhibited by CP-25 in a concentration-dependent manner. In vivo administration of CP-25 alleviated adjuvant arthritis (AA) in rats through inhibition of DC maturation and activation. Our results indicate that PGE2-EP4-cAMP signal hyperfunction can lead to abnormal activation of DC functions, which correlates with the course of disease in AA rats and provides a possible treatment target. The inhibition of DC maturation and activation by CP-25 interference of the PGE2-EP4 pathway may significantly contribute to the immunoregulatory profile of CP-25 when used to treat RA and other immune cell-mediated disorders.
KeywordsAdjuvant-induced arthritis Paeoniflorin-6′-O-benzene sulfonate Dendritic cell PGE2 EP receptor cAMP
Rat adjuvant-induced arthritis
Bone marrow-derived DCs
Complete Freund’s adjuvant
Disease-modifying antirheumatic drugs
Enzyme-linked immunosorbent assay
Fetal calf serum
Mixed lymphocyte reaction;
Quantification via real-time PCR
Tumor necrosis factor-α
Total glucosides of peony
This work was supported by the National Natural Science Foundation of China (81330081, 31200675, 81573443, 81603362), by the Anhui Province Nature Science Foundation in the University (KJ2015A317), by Anhui Province Natural Science Fund (outstanding youth) (170808J10).
WW and YC conceived and designed the study. XYJ designed and performed most of the experiments, and wrote the manuscript. FW, XD, XJS, SX and XZY performed experiments. YJW carried out the flow cytometry assays and helped to revise the manuscript. HXW and CW participated in the design of the study and helped to revise the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
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