title: Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: regulation of synovial proliferation and inflammatory gene expression.
abstract: OBJECTIVE
  Sphingosine 1-phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P1 signaling in the pathogenesis of rheumatoid arthritis (RA).
  
  
  METHODS
  We examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting. We also performed S1P1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST-1 assay, and its effects on tumor necrosis factor alpha (TNFalpha)- or interleukin-1beta (IL-1beta)-induced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production in RA synoviocytes and MH7A cells by Western blotting and enzyme-linked immunosorbent assay, respectively. Finally, we examined whether these effects of S1P were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins.
  
  
  RESULTS
  S1P1 mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P1 was more strongly expressed in synovial lining cells, vascular endothelial cells, and inflammatory mononuclear cells of RA synovium compared with OA synovium. S1P increased the proliferation of RA synoviocytes and MH7A cells. S1P alone significantly enhanced COX-2 expression and PGE2 production. Moreover, S1P enhanced expression of COX-2 and production of PGE2 induced by stimulation with TNFalpha or IL-1beta in RA synoviocytes and MH7A cells. These effects of S1P were inhibited by pretreatment with PTX.
  
  
  CONCLUSIONS
  These findings suggest that S1P signaling via S1P receptors plays an important role in cell proliferation and inflammatory cytokine-induced COX-2 expression and PGE2 production by RA synoviocytes. Thus, regulation of S1P/S1P1 signaling may represent a novel therapeutic target in RA.
authors.affiliation: Hyogo College of Medicine, Nishinomiya-city, Hyogo, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kitano
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawahito
authors.forename: Rikio
authors.initials: R
authors.lastname: Yoshimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Hajime
authors.initials: H
authors.lastname: Sano
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
authors.forename: Yuen Yee
authors.initials: YY
authors.lastname: Tam
mesh_terms: D001172:Arthritis, Rheumatoid / Q000473:pathology*; D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D008246:Lysophospholipids / Q000032:analysis / Q000502:physiology*; D008565:Membrane Proteins / Q000032:analysis; D010003:Osteoarthritis / Q000473:pathology; D037342:Pertussis Toxin / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D049349:Receptors, Lysosphingolipid / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000502:physiology; D013583:Synovial Membrane / Q000473:pathology*; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D008246:Lysophospholipids; D008565:Membrane Proteins; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D037342:Pertussis Toxin; D015232:Dinoprostone; D013110:Sphingosine