TAK-242 (Resatorvid) inhibits proinflammatory cytokine production through the inhibition of NF-κB signaling pathway in fibroblast-like synoviocytes in osteoarthritis patients.
{"title":"TAK-242 (Resatorvid) inhibits proinflammatory cytokine production through the inhibition of NF-κB signaling pathway in fibroblast-like synoviocytes in osteoarthritis patients.","authors":"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","doi":"10.1186/s42358-024-00385-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Materials and methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":48634,"journal":{"name":"Advances in Rheumatology","volume":"64 1","pages":"46"},"PeriodicalIF":2.0000,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advances in Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s42358-024-00385-9","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.