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Sphingosine-1-phosphate mediates fibrosis in orbital fibroblasts in graves’ orbitopathy

Other Titles
 갑상샘눈병증 환자의 안와 섬유모세포에서 섬유화에 대한 sphingosine-1-phosphate의 역할 
Authors
 고재상 
Department
 Dept. of Ophthalmology (안과학교실) 
Degree
박사
Issue Date
2018
Description
의학과/박사
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 transforming growth factor (TGF)-β and cigarette smoke extract (CSE) on S1P receptor (S1PR) messenger RNAs (mRNA) were evaluated by real-time polymerase chain reaction. 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 h before stimulation with TGF-β, CSE, or interleukin (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 mRNAs 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 pro-fibrotic stimulants upregulated collagen Iα, fibronectin, α-SMA, MMP-1, MMP-2, MMP-9, and TIMP-1 expression in a dose-dependent manner. Conclusion: 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.
Files in This Item:
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 3. Dissertation
Yonsei Authors
Ko, Jaesang(고재상) ORCID logo https://orcid.org/0000-0002-3011-7213
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/166449
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