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.