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. PR-957 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 RA-FLS 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.

 

Comments:

The study you've outlined seems comprehensive in evaluating the effects of PR-957, an anti-LMP7 agent, on rheumatoid arthritis (RA) both in vitro and in vivo. Here's a breakdown of the key findings:

### Objective:
- Investigate the impact of PR-957, an anti-LMP7 agent, on RA treatment by targeting LMP7-mediated CD4+ T cell imbalance.

### Methods:

1. **Sample Collection:** PBMCs from 30 RA patients and 30 healthy controls were obtained.

2. **Isolation:** RA fibroblast-like synoviocytes (RA-FLSs) and CD4+ T cells were isolated from RA patients.

3. **Experimental Setup:**
   - Coculture of CD4+ T cells and RA-FLSs with PR-957 and/or LMP7 overexpression adenovirus (Ad-LMP7).
   - Construction of collagen-induced arthritis (CIA) mice treated with PR-957 and/or Ad-LMP7.

### Results:
1. **LMP7 Levels:** Higher in RA patients than in healthy controls.
2. **Correlation:**
   - Positively correlated with Th1 cells, Th1/Th2 ratio, Th17 cells, and Th17/Treg ratio, but not with Th2 or Treg cells.
3. **Effects of PR-957:**
   - Reduced Th1 and Th17 cells but increased Th2 and Treg cells in RA-CD4+ T cells.
   - Increased RA-FLS apoptosis, decreased invasive ability, viability, and inflammation when cocultured with RA-CD4+ T cells.
4. **In CIA Mice:**
   - PR-957 decreased arthritis score, synovial hyperproliferation, articular injury, synovial and serum inflammation, and imbalance of Th1/Th2 and Th17/Treg in the spleen.

### Conclusion:
- PR-957 shows promise in ameliorating RA progression and inflammation by targeting LMP7-mediated CD4+ T cell imbalance.
- Ad-LMP7 transfection attenuated the effects of PR-957, suggesting LMP7's involvement in these processes.

This study's results indicate the therapeutic potential of PR-957 in mitigating RA by modulating CD4+ T cell responses via LMP7 regulation. Further research could delve into the specific molecular mechanisms underlying these interactions and validate the therapeutic potential in clinical settings.

Related Products

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S7172	ONX-0914 (PR-957)	ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay.

Related Targets

Proteasome