Abstract
Fibroblast-like synoviocytes (FLSs), the main pathological cells in rheumatoid arthritis (RA), display tumor-like phenotype, including hyper-proliferation, apoptosis resistance, and aggressive phenotype. Excessive proliferation and insufficient apoptosis of RA-FLSs can lead to hyperplastic synovial pannus tissue, excess production of inflammatory mediators, and destruction of joints. In this article, we investigate the effect of PRIMA-1MET on the apoptosis induction and inhibition of pro-inflammatory cytokines in RA-FLSs. Synovial tissue samples were obtained from 10 patients with RA. The FLSs were treated with different concentrations of PRIMA-1MET. The rate of apoptosis and cell survival was assessed by flow cytometry and MTT assay and Real-time quantitative PCR was performed to evaluate the transcription of p53, IL-6, IL-1β, TNF-α, Noxa, p21, PUMA, Bax, Survivin, and XIAP in treated RA-FLSs. The protein level of p53, IκBα, and phospho-IκBα were measured using Western blotting. The results showed that PRIMA-1MET induced apoptosis in RA-FLSs and increased significantly the expression of Noxa, and decreased significantly IL-6, IL-1β, p53, and phospho-IκBα expression. PRIMA-1MET can induce apoptosis in RA-FLSs through induction of Noxa expression while p53 was downregulated. Furthermore, PRIMA-1MET treatment results in the suppression of pro-inflammatory cytokine production and NF-κB inhibition. Given the role of p53 and NF-κB in RA-FLSs, PRIMA-1MET can be considered as a new therapeutic strategy for rheumatoid arthritis.
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The data generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Applicable on requested.
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This study was supported by a grant from Tehran University of Medical Sciences (Grant No: 97-03-41-40374), and a grant from Kermanshah University of Medical Sciences (Grant No: 97887).
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MA: acquisition of data, drafting the article, analysis and interpretation of data, final approval of the article. MNT and AS: acquisition of clinical data and patient’s diagnosis and treatment, interpretation of data, drafting the article, and final approval of the article. MT, AJ, MM and EF: the conception and design of the study, revising the article critically, interpretation of data, final approval of the article.
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Adib, M., Taghadosi, M., Tahmasebi, M.N. et al. Anti-inflammatory effects of PRIMA-1MET (mutant p53 reactivator) induced by inhibition of nuclear factor-κB on rheumatoid arthritis fibroblast-like synoviocytes. Inflammopharmacol 31, 385–394 (2023). https://doi.org/10.1007/s10787-022-01094-9
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DOI: https://doi.org/10.1007/s10787-022-01094-9