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Sphingosine-1-Phosphate Mediates Fibrosis in Orbital Fibroblasts in Graves' Orbitopathy

 JaeSang Ko  ;  Min Kyoung Chae  ;  Joon H. Lee  ;  Eun Jig Lee  ;  Jin Sook Yoon 
 Investigative Ophthalmology & Visual Science, Vol.58(5) : 2544-2553, 2017 
Journal Title
 Investigative Ophthalmology & Visual Science 
Issue Date
Adult ; Blotting, Western ; Cells, Cultured ; Female ; Fibroblasts/metabolism ; Fibroblasts/pathology* ; Fibrosis/genetics ; Fibrosis/metabolism ; Fibrosis/pathology ; Gene Expression Regulation* ; Graves Ophthalmopathy/genetics* ; Graves Ophthalmopathy/metabolism ; Graves Ophthalmopathy/pathology ; Humans ; Lysophospholipids/biosynthesis ; Lysophospholipids/genetics* ; Male ; Middle Aged ; RNA/genetics* ; Real-Time Polymerase Chain Reaction ; Signal Transduction ; Sphingosine/analogs & derivatives* ; Sphingosine/biosynthesis ; Sphingosine/genetics
Purpose: To investigate the effect of sphingosine-1-phosphate (S1P) on fibrosis in orbital fibroblasts in Graves' orbitopathy (GO). Methods: Orbital fibroblasts were cultured from orbital adipose/connective tissues of patients with GO and healthy control subjects. Effects of treatment with TGF-β and cigarette smoke extract (CSE) on S1P receptor (S1PR) messenger RNA (mRNA) and S1P expression were evaluated by real-time polymerase chain reaction and Western blotting. To evaluate the role of S1P in fibrosis, cells were pretreated with W146 (S1PR1 antagonist); JTE013 (S1PR2 antagonist); FTY720 (S1PR1 modulator); or 5C (sphingosine kinase-1 blocker) for 1 hour before stimulation with TGF-β, CSE, or IL-1β. Expression of fibrosis-related proteins (collagen Iα, fibronectin, and α-smooth muscle actin [SMA]) and tissue remodeling-related proteins (matrix metalloproteinases [MMPs] and tissue inhibitor of metalloproteinase [TIMP]-1) was then evaluated by Western blotting. Results: Expression levels of S1PR mRNA and S1P in GO orbital fibroblasts increased upon TGF-β and CSE treatment. Treatment with S1PR blockers and 5C inhibited TGF-β and CSE-induced expression of collagen Iα, fibronectin, and α-SMA, as well as IL-1β-induced expression of MMP-1, MMP-2, MMP-9, and TIMP-1. Exogenous S1P treatment without profibrotic stimulants upregulated collagen Iα, fibronectin, α-SMA, MMP-1, MMP-2, MMP-9, and TIMP-1 expression in a dose-dependent manner. Conclusions: Blocking of S1PR activity and inhibition of S1P synthesis led to decreased expression of fibrosis and tissue remodeling-related proteins in primary cultures of orbital fibroblasts derived from patients with GO. Thus, modulation of S1P activity might have therapeutic potential in the suppression of fibrosis in GO.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
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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