Home Blog of Signal Transduction Proteases Proteasome PR-957 retards rheumatoid arthritis progression and inflammation by inhibiting LMP7-mediated CD4+ T cell imbalance

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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

Cat.No. Product Name Information
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.

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Proteasome