CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents

Abstract

Paeoniflorin-6′-O-benzene sulfonate (code: CP-25) was the chemistry structural modifications of Paeoniflorin (Pae). CP-25 inhibited B cells proliferation stimulated by B cell activating factor belonging to the TNF family (BAFF) or Tumor necrosis factor alpha (TNF-alpha). CP-25, Rituximab and Etanercept reduced the percentage and numbers of CD19+ B cells, CD19+CD20+ B cells, CD19+CD27+ B cells and CD19+CD20+CD27+ B cells induced by BAFF or TNF-alpha. There was significant difference between CP-25 and Rituximab or CP-25 and Etanercept. CP-25 down-regulated the high expression of BAFFR, BCMA, and TACI stimulated by BAFF or TNF-alpha. The effects of Rituximab and Etanercept on BAFFR or BCMA were stronger than that of CP-25. CP-25, Rituximab and Etanercept down-regulated significantly the expression of TNFR1 and TNFR2 on B cell stimulated by BAFF or TNF-alpha. CP-25, Rituximab and Etanercept down-regulated the expression of MKK3, P-p38, P-p65, TRAF2, and p52 in B cells stimulated by BAFF and the expression of TRAF2 and P-p65 in B cells stimulated by TNF-alpha. These results suggest that CP-25 regulated moderately activated B cells function by regulating the classical and alternative NF-κB signaling pathway mediated by BAFF and TNF-alpha-TRAF2-NF-κB signaling pathway. This study suggests that CP-25 may be a promising anti-inflammatory immune and soft regulation drug.

Etanercept Inhibits B Cell Differentiation by Regulating TNFRII/TRAF2/NF-κB Signaling Pathway in Rheumatoid Arthritis

“…The increase in the number of circulating B cells may be owing to the continuous activation of B cells (Lindenau et al, 2003). Previous studies by our team have found that abnormal activation of B cells does exist in RA patients (Zhang et al, 2017). This study showed that the percentage of CD19 + total B cells, CD19 + CD27 + memory B cells, and CD19 − CD27 + CD138 + plasma B cells, the levels of TNF-a, BAFF, laboratory parameters, and clinical indicators of RA patients all decreased after etanercept treatment.…”

“…Further, B cells produce receptor activator of NF-kB ligand (RANKL) near the osteoclast precursors and promote bone destruction in a RANKL dependent way within synovium ectopic lymphoid structures (Sun et al, 2018). A previous study of our research group proved that abnormal activation of B cells participates in the pathological process of RA (Zhang et al, 2017). B cell activating factor (BAFF) belongs to the tumor necrosis factor superfamily, which is a crucial factor for B cell survival and maturation (Shin et al, 2018).…”

A Modified Compound From Paeoniflorin, CP-25, Suppressed Immune Responses and Synovium Inflammation in Collagen-Induced Arthritis Mice

“…Our previous study found that CP-25 inhibited activated human B cells by regulating B-cell activating factor and TNF-α signaling. Compared with the effects of rituximab and etanercept, CP-25 showed modest activity, suggesting that CP-25 may provide a promising approach to the soft regulation of inflammation ( Zhang et al, 2017 ).…”

Emerging small-molecule treatments for multiple sclerosis: focus on B cells

“…CP-25 is a derivative of the natural product paeoniflorin 130 , which is able to inhibit B-cell proliferation in a similar manner to rituximab (CD20 B-cell targeting antibody) and etanercept (TNF receptor chimera) and also downregulate the expression of BAFF-R on B cells. The mechanism of these effects is not reported 131 . It will be interesting to note the progression of this compound and ones with a similar mode of action.…”