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

IF 2 4区 医学 Q3 RHEUMATOLOGY Advances in Rheumatology Pub Date : 2024-06-07 DOI:10.1186/s42358-024-00385-9
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
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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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TAK-242 (Resatorvid) 通过抑制骨关节炎患者成纤维细胞样滑膜细胞中的 NF-κB 信号通路,抑制促炎细胞因子的产生。
背景:成纤维细胞样滑膜细胞(FLS)通过产生促炎细胞因子参与骨关节炎(OA)的发病机制。TAK-242是一种TLR4阻断剂,已被发现对OA-FLSs中IL1-β、IL-6、TNF-α和TLR4等促炎细胞因子的基因表达谱以及NF-κB信号通路调节因子Ikβα的磷酸化有显著影响。由于TLR4在炎症反应中起着至关重要的作用,本研究旨在探讨这一效应:为了评估 TAK-242 的有效性,研究人员采集了 10 例 OA 患者的滑膜组织,并在 DMEM 中培养分离出的 FLSs。用 Real-Time PCR 分析经 TAK-242 和脂多糖(LPS)处理的 FLSs 的 IL1-β、IL-6、TNF-α 和 TLR4 的 mRNA 表达水平。此外,我们还利用 Western 印迹技术评估了 Ikβα 和 pIkβα 的蛋白水平:结果表明,TAK-242能有效抑制LPS处理后过表达的炎性细胞因子IL1-β、IL-6、TNF-α和TLR4的基因表达。此外,TAK-242 还能抑制因 LPS 处理而增加的 Ikβα 磷酸化:根据我们的研究结果,TAK-242 通过靶向 NF-κB 通路,对 TLR4 介导的 OA-FLSs 炎症反应具有良好的抑制作用。TLR4抑制剂(如TAK-242)可能是减少OA患者炎症及其相关并发症的有效治疗药物,因为传统疗法和生物疗法可能并不适用于所有OA患者。
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来源期刊
Advances in Rheumatology
Advances in Rheumatology Medicine-Rheumatology
CiteScore
4.00
自引率
4.30%
发文量
41
审稿时长
53 weeks
期刊介绍: Formerly named Revista Brasileira de Reumatologia, the journal is celebrating its 60th year of publication. Advances in Rheumatology is an international, open access journal publishing pre-clinical, translational and clinical studies on all aspects of paediatric and adult rheumatic diseases, including degenerative, inflammatory and autoimmune conditions. The journal is the official publication of the Brazilian Society of Rheumatology and welcomes original research (including systematic reviews and meta-analyses), literature reviews, guidelines and letters arising from published material.
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