title: Role of sphingosine 1-phosphate in the pathogenesis of Sjögren's syndrome.
abstract: Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammatory mononuclear cell infiltration and destruction of epithelial cells of lacrimal and salivary glands. Sphingosine 1-phosphate (S1P) and signaling through its receptor S1P(1) have been implicated in many critical cellular events including inflammation, cancer, and angiogenesis. This study was undertaken to examine the role of S1P(1) signaling in the pathogenesis of primary SS. S1P(1) and sphingosine kinase 1, which converts sphingosine to S1P, were detected in the cytoplasm of inflammatory mononuclear cells, vascular endothelial cells, and epithelial cells in all labial salivary glands by immunohistochemistry. The expression of S1P(1) in inflammatory mononuclear cells was enhanced in advanced stages of primary SS. S1P enhanced proliferation and IFN-gamma production by CD4(+) T cells. The enhancing effect of S1P on IFN-gamma production by CD4(+) T cells was stronger in patients with primary SS than in healthy controls. S1P also enhanced Fas expression and Fas-mediated caspase-3 induction in salivary gland epithelial cells. IL-6 expression was detected in the cytoplasm of inflammatory mononuclear cells and ductal epithelial cells and was enhanced in advanced stages of primary SS. Furthermore, both IFN-gamma and S1P augmented IL-6 secretion by salivary gland epithelial cells. These effects of S1P were inhibited by pretreatment of pertussis toxin. Our data reveal that S1P(1) signaling may modulate the autoimmune phenotype of primary SS by the action of immune as well as epithelial cells.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kitano
authors.forename: Hideki
authors.initials: H
authors.lastname: Kuno
authors.forename: Naoaki
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawahito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.forename: Hajime
authors.initials: H
authors.lastname: Sano
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D053148:Caspase 3 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation; D008246:Lysophospholipids / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000032:analysis / Q000378:metabolism*; D012469:Salivary Glands / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D019014:fas Receptor; C060506:sphingosine 1-phosphate; D007371:Interferon-gamma; D053148:Caspase 3; D013110:Sphingosine