TAK-242 (Resatorvid) inhibits proinflammatory cytokine production through the inhibition of NF-κB signaling pathway in fibroblast-like synoviocytes in osteoarthritis patients

Autor: Mohammadreza Khomeijani-Farahani, Jafar karami, Elham Farhadi, Samaneh Soltani, Ali-Akbar Delbandi, Mehdi Shekarabi, Mohammad Naghi Tahmasebi, Arash Sharafat Vaziri, Ahmadreza Jamshidi, Mahdi Mahmoudi, Masoomeh Akhlaghi
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Advances in Rheumatology, Vol 64, Iss 1, Pp 1-9 (2024)
Druh dokumentu: article
ISSN: 2523-3106
DOI: 10.1186/s42358-024-00385-9
Popis: Abstract Background Fibroblast-like synoviocytes (FLSs) are involved in osteoarthritis (OA) pathogenesis through pro-inflammatory cytokine production. TAK-242, a TLR4 blocker, has been found to have a significant impact on the gene expression profile of pro-inflammatory cytokines such as IL1-β, IL-6, TNF-α, and TLR4, as well as the phosphorylation of Ikβα, a regulator of the NF-κB signaling pathway, in OA-FLSs. This study aims to investigate this effect because TLR4 plays a crucial role in inflammatory responses. Materials and methods Ten OA patients’ synovial tissues were acquired, and isolated FLSs were cultured in DMEM in order to assess the effectiveness of TAK-242. The treated FLSs with TAK-242 and Lipopolysaccharides (LPS) were analyzed for the mRNA expression level of IL1-β, IL-6, TNF-α, and TLR4 levels by Real-Time PCR. Besides, we used western blot to assess the protein levels of Ikβα and pIkβα. Results The results represented that TAK-242 effectively suppressed the gene expression of inflammatory cytokines IL1-β, IL-6, TNF-α, and TLR4 which were overexpressed upon LPS treatment. Additionally, TAK-242 inhibited the phosphorylation of Ikβα which was increased by LPS treatment. Conclusion According to our results, TAK-242 shows promising inhibitory effects on TLR4-mediated inflammatory responses in OA-FLSs by targeting the NF-κB pathway. TLR4 inhibitors, such as TAK-242, may be useful therapeutic agents to reduce inflammation and its associated complications in OA patients, since traditional and biological treatments may not be adequate for all of them.
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