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

Authors
 JaeSang Ko  ;  Min Kyoung Chae  ;  Joon H. Lee  ;  Eun Jig Lee  ;  Jin Sook Yoon 
Citation
 Investigative Ophthalmology & Visual Science, Vol.58(5) : 2544-2553, 2017 
Journal Title
 Investigative Ophthalmology & Visual Science 
ISSN
 0146-0404 
Issue Date
2017
MeSH
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
Abstract
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.
Full Text
http://iovs.arvojournals.org/article.aspx?articleid=2626986
DOI
10.1167/iovs.16-20684
Appears in Collections:
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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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/160369
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