PR-957 retards rheumatoid arthritis progression and inflammation by inhibiting LMP7-mediated CD4⁺ T cell imbalance

Objective: Low molecular mass polypeptide 7 (LMP7) is an immunoproteasome subunit that regulates T cell amplification, differentiation, and inflammation and is involved in rheumatoid arthritis (RA) progression. This study intended to apply PR-957 (an anti-LMP7 agent) for RA treatment in vitro and in vivo and evaluate its interaction with LMP7-mediated CD4(+) T cell imbalance.Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 30 RA patients and 30 healthy controls. RA fibroblast-like synoviocytes (RA-FLSs) and CD4(+) T cells were isolated from RA patients and then cocultured with PR-957 and/or LMP7 overexpression adenovirus (Ad-LMP7). Collagen-induced arthritis (CIA) mice were constructed and then treated with PR-957 and/or Ad-LMP7.Results: LMP7 was higher in RA patients (versus healthy controls) and positively correlated with T helper (Th)1 cells, the Th1/Th2 ratio, Th17 cells, and the Th17/Treg ratio but not with Th2 or T regulatory (Treg) cells. PR957 reduced Th1 and Th17 cells but increased Th2 and Treg cells in RA-CD4(+) T cells, and this effect was partially reversed by Ad-LMP7 transfection. Interestingly, when cocultured with RA-CD4(+) T cells, PR-957 increased RAFLS apoptosis and decreased its invasive ability, viability, and inflammation, as suggested by IL-6, CCL2, MMP1, and MMP3; however, these phenomena were weakened in RA-FLSs without RA-CD4(+) T cell coculture. In addition, Ad-LMP7 transfection attenuated the above effects of PR-957. In CIA mice, PR-957 decreased the arthritis score, synovial hyperproliferation and articular injury, inflammation in the synovium and serum, and the imbalance of Th1/Th2 and Th17/Treg in the spleen, and these effects were attenuated by Ad-LMP7.Conclusion: PR-957 ameliorates RA progression and inflammation by repressing LMP7-mediated CD4(+) T cell imbalance.