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Inhibitory Effect of Idelalisib, a Selective Phosphatidylinositol 3-Kinase δ Inhibitor, on Adipogenesis in an In Vitro Model of Graves' Orbitopathy.

Authors
 JaeSang Ko  ;  Ji-Young Kim  ;  Eun Jig Lee  ;  Jin Sook Yoon 
Citation
 Investigative Ophthalmology & Visual Science, Vol.59(11) : 4477-4485, 2018 
Journal Title
 Investigative Ophthalmology & Visual Science 
ISSN
 0146-0404 
Issue Date
2018
Keywords
adipogenesis ; Graves’ orbitopathy ; idelalisib ; orbital fibroblast ; phosphatidylinositol 3-kinase
Abstract
Purpose: Emerging evidence indicates that the phosphatidylinositol 3-kinase (PI3K)-AKT pathway is involved in the pathogenesis of Graves' orbitopathy (GO). In this study, the therapeutic effects of idelalisib, a selective PI3Kδ inhibitor, on adipogenesis were evaluated in GO orbital fibroblasts in vitro. Methods: Orbital fibroblasts were cultured from orbital connective tissues obtained from individuals with GO and healthy control subjects. Cells were pretreated with idelalisib for 1 hour before stimulation with IL-1β. Inflammatory cytokine expression was measured by Western blotting and ELISAs. The adipogenesis-related downstream mediators of the PI3K/AKT cascade, that is, forkhead box protein O1 (FOXO1) and mammalian target of rapamycin (mTOR), also were measured by Western blotting. After adipogenic differentiation and idelalisib treatment, cells were stained with Oil Red O and the levels of peroxisome proliferator activator γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBP) α/β were determined by Western blot analyses. Results: AKT phosphorylation decreased in a dose-dependent manner upon treatment with idelalisib in GO and non-GO orbital fibroblasts. Treatment with idelalisib inhibited the IL-1β-induced expression of IL-6 and IL-8. Idelalisib attenuated the phosphorylation of mTOR and FOXO1, downstream regulators of the PI3K pathway. Oil Red-O staining results revealed a decrease in lipid droplets and suppressed expression of PPARγ and c/EBPα/β upon treatment with idelalisib during adipose differentiation. Conclusions: Idelalisib inhibited proinflammatory cytokine production and adipogenesis in GO orbital fibroblasts in vitro. These results support the potential use of PI3K inhibitors in GO management.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163489
DOI
10.1167/iovs.18-24509
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
Yonsei Authors
고재상(Ko, Jaesang) ORCID logo https://orcid.org/0000-0002-3011-7213
윤진숙(Yoon, Jin Sook) ORCID logo https://orcid.org/0000-0002-8751-9467
이은직(Lee, Eun Jig) ORCID logo https://orcid.org/0000-0002-9876-8370
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