title: Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves' orbitopathy.
abstract: OBJECTIVE
  Graves' orbitopathy (GO) is initiated by excessive amount of various inflammatory mediators produced by orbital fibroblasts. This study aimed to assess the crucial role of sphingosine-1-phosphate (S1P) in the inflammatory process of GO.
  
  
  METHODS
  Orbital adipose/connective tissue samples were obtained from 10 GO patients and 10 normal control individuals during surgery. Primary orbital fibroblast culture was done. After the expression of S1P receptors and sphingosine kinase (SphK) was assessed with the treatment of interleukin (IL)-1β, we evaluated the expression of pro-inflammatory factors [intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and IL-6] after treating S1P. S1P receptor antagonists and SphK 1 inhibitor were pretreated and the expression of the pro-inflammatory factors was assessed.
  
  
  RESULTS
  IL-1β exacerbated the inflammatory process by enhancing the expression of S1P receptors and SphK in GO orbital fibroblasts. IL-1β also induced the expressions of ICAM-1, COX-2, and IL-6 in GO orbital fibroblasts, and these expressions were effectively inhibited by S1P receptor antagonists and SphK1 inhibitor.
  
  
  CONCLUSIONS
  S1P has an important role in the pathological inflammatory process of GO, which is mediated through the SphK1-S1P- S1P receptor pathway. SphK1 inhibitors and S1P receptors or antagonists could be potential approaches for controlling the inflammatory process of GO.
authors.affiliation: Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Chae
authors.affiliation: Kyunghee University College of Medicine, Seoul, South Korea.
authors.forename: Sol Ah
authors.initials: SA
authors.lastname: Han
authors.affiliation: Department of Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Nonsan, South Korea. joonhlee@konyang.ac.kr.
authors.forename: Joon H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea. yoonjs@yuhs.ac.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Yoon
mesh_terms: D000328:Adult; D000368:Aged; D003238:Connective Tissue / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D049970:Graves Ophthalmopathy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D051546:Cyclooxygenase 2; D053583:Interleukin-1beta; D015850:Interleukin-6; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C508600:IL6 protein, human; C060506:sphingosine 1-phosphate; C496540:PTGS2 protein, human
keywords: Graves’ orbitopathy; Inflammation; Orbital fibroblasts; S1P receptor antagonist; Sphingosine-1-phosphate