Tak-242 (Resatorvid) Inhibits Proinflammatory Cytokine Production Through the Inhibition of Nf-Κb Signaling Pathway in Fibroblast-Like Synoviocytes in Osteoarthritis Patients Publisher Pubmed



Khomeijanifarahani M^{1, 2} ; Karami J^{1, 3} ; Farhadi E^{1, 4} ; Soltani S¹ ; Delbandi AA^{5, 6} ; Shekarabi M^{5, 6} ; Tahmasebi MN⁷ ; Vaziri AS⁷ ; Jamshidi A¹ ; Mahmoudi M^{1, 4} ; Akhlaghi M^{1, 4, 8} Show Affiliations
Source: Advances in Rheumatology Published:2024

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. © The Author(s) 2024.