Glycogen Synthase Kinase-3β Mediates Proinflammatory Cytokine Secretion and Adipogenesis in Orbital Fibroblasts from Patients with Graves' Orbitopathy

Jihei Sara Lee, Min Kyoung Chae, Don O. Kikkawa, Eun Jig Lee, Jin Sook Yoon

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7 Citations (Scopus)


PURPOSE. We sought to determine the role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Graves' orbitopathy(GO). METHODS. Expression of the GSK-3β 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-3β 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 (PPARγ ) and CCAAT-enhancer-binding proteins (C/EBPs) α and β were determined by western blot. RESULTS. The expression of GSK-3β 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-1β or TNF-α, 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)-κB, Erk, Jnk, and p38 kinase by IL-1β and TNF-α was diminished with CHIR 99021 in GO cells. A decrease in lipid droplets and expression of PPARγ and c/EBPα and-β was noted in fibroblasts treated with CHIR 99021 during adipocyte differentiation. The inhibition of Wnt and β-catenin in adipogenesis was reversed by CHIR 99021. CONCLUSIONS. GSK-3β plays a significant role in GO pathogenesis. The inhibition of the kinase attenuated the proinflammatory cytokines production and fibroblast differentiation into adipocytes. GSK-3β may be a potential target for anti-inflammatory and antiadipogenic treatment of GO.

Original languageEnglish
Article number51
JournalInvestigative Ophthalmology and Visual Science
Issue number8
Publication statusPublished - 2020 Jul

Bibliographical note

Publisher Copyright:
© 2020 Association for Research in Vision and Ophthalmology Inc.. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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