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

Autor: Khomeijani-Farahani M; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.; Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran., Karami J; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.; Molecular and Medicine Research Center, Khomein University of Medical Sciences, Khomein, Iran., Farhadi E; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.; Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran., Soltani S; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Delbandi AA; Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran., Shekarabi M; Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. shekarabi.m@iums.ac.ir.; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran. shekarabi.m@iums.ac.ir., Tahmasebi MN; Department of Orthopedics, Division of Knee Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran., Vaziri AS; Department of Orthopedics, Division of Knee Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran., Jamshidi A; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Mahmoudi M; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran. mahmoudim@tums.ac.ir.; Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran. mahmoudim@tums.ac.ir., Akhlaghi M; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran. makhlaghi@tums.ac.ir.; Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran. makhlaghi@tums.ac.ir.; Rheumatology Research Center, Shariati Hospital, Kargar Ave., Tehran, Iran. makhlaghi@tums.ac.ir.
Jazyk: angličtina
Zdroj: Advances in rheumatology (London, England) [Adv Rheumatol] 2024 Jun 07; Vol. 64 (1), pp. 46. Date of Electronic Publication: 2024 Jun 07.
DOI: 10.1186/s42358-024-00385-9
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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