CP-25

B cell activating factor (BAFF) has been shown to play a key role in regulating B cell function, but little is known about whether BAFF affects the function of fibroblast-like synoviocyte (FLS), an effector cell of rheumatoid arthritis (RA). CP-25, a new ester derivative of paeoniflorin, could alleviate the arthritis symptoms of collagen-induced arthritis (CIA) mice by inhibiting BAFF-mediated abnormal activation of B cells. In this study, we aimed to understand the mechanism by which BAFF activates FLS and the effect of CP-25 on FLS function. Therefore, the proliferation and migration abilities of FLS and key proteins on the non-canonical NF-κB pathway were examined. The results showed that compared with the FLS of normal rats/OA patients, the expression of BAFF-R, TRAF2, NIK, p-IKKα, P100, and P52 was higher in the FLS of AA rats/RA patients, while the expression of TRAF3 was lower. And, BAFF promotes FLS activation by activating the non-canonical NF-κB signaling pathway. Meanwhile, BAFFR-siRNA inhibited the proliferation of FLS and the activation of non-canonical NF-κB signaling in FLS induced by BAFF. Additionally, CP-25 could inhibit abnormal proliferation and migration of FLS by regulating non-canonical NF-κB signaling. We concluded that BAFF may act as an important role in facilitating the function of FLS through the BAFFR-mediated non-canonical NF-κB pathway, which would be useful for revealing the pathological mechanism of RA. And CP-25 may become a potential new drug for the treatment of RA, providing a scientific basis for the development of new drugs to treat RA.

Peoniflorin‐6′‐O‐benzene sulfonate (CP‐25) inhibited the activity of GRK2 to exert anti‐inflammatory and immunomodulatory effects. This study aimed to investigate the effect of CP‐25 the intestinal epithelial barrier and the mechanism. CaCO‐2 cell monolayer and dextran sulfate salt (DSS)‐induced colitis mouse model was used to evaluate intestinal epithelial barrier function in vitro and in vivo, respectively. Results showed that CP‐25 prevented dysfunction of the intestinal epithelial barrier and inhibited NF‐κB p65 activation in TNF‐α‐induced CaCO‐2 cells. The colon structure destroyed in DSS‐induced colitis mice was improved by CP‐25. CP‐25 has a role in inhibition membrane translocation of GRK2‐β‐arrestin 2 complex, stabilization of the binding of GRK2 and β‐arrestin 2 to ERK1/2 in cytoplasm. Subsequently down‐regulated the nuclear transcription and transactivation of NF‐κB p65 via inhibiting its phosphorylation of Ser536, and Ser276, respectively and restored the epithelial barrier function. In conclusion, CP‐25 inhibited ERK1/2‐NF‐κB activation and thereby protected the intestinal epithelial barrier, which was associated with restoring the inhibition of GRK2 and β‐arrestin 2 on ERK1/2.