Glycogen Synthase Kinase-3? Mediates Proinflammatory Cytokine Secretion and Adipogenesis in Orbital Fibroblasts from Patients with Graves' Orbitopathy.
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ABSTRACT: Purpose:We sought to determine the role of glycogen synthase kinase-3? (GSK-3?) in the pathogenesis of Graves' orbitopathy(GO). Methods:Expression of the GSK-3? gene in whole orbital tissue explants was compared between GO and non-GO donors using quantitative real-time PCR (RT-PCR). The expression of proinflammatory molecules in the presence of the GSK-3? inhibitor CHIR 99021 was analyzed using RT-PCR, western blot, and ELISA. Adipogenic differentiation was identified using Oil Red O staining, and the levels of peroxisome proliferator activator gamma (PPAR?) and CCAAT-enhancer-binding proteins (C/EBPs) ? and ? were determined by western blot. Results:The expression of GSK-3? was significantly higher in GO tissues than in control tissues. The addition of CHIR 99021 led to a decrease in the active form of the kinase in which the Y216 residue is phosphorylated. When GO and non-GO fibroblasts were stimulated with IL-1? or TNF-?, IL-6, IL-8, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-1 (COX-1), and monocyte chemoattractant protein 1 (MCP-1) showed increased production, which was blunted when CHIR 99021 was added. The activation of Akt, PI3K, nuclear factor (NF)-?B, Erk, Jnk, and p38 kinase by IL-1? and TNF-? was diminished with CHIR 99021 in GO cells. A decrease in lipid droplets and expression of PPAR? and c/EBP? and -? was noted in fibroblasts treated with CHIR 99021 during adipocyte differentiation. The inhibition of Wnt and ?-catenin in adipogenesis was reversed by CHIR 99021. Conclusions:GSK-3? plays a significant role in GO pathogenesis. The inhibition of the kinase attenuated the proinflammatory cytokines production and fibroblast differentiation into adipocytes. GSK-3? may be a potential target for anti-inflammatory and anti-adipogenic treatment of GO.
SUBMITTER: Lee JS
PROVIDER: S-EPMC7426624 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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