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Role of Sphingosine 1-Phosphate in the Pathogenesis of Sjögren’s Syndrome¹

Masahiro Sekiguchi^*, Tsuyoshi Iwasaki^2,*, Masayasu Kitano^*, Hideki Kuno^*, Naoaki Hashimoto^*, Yutaka Kawahito, Masayuki Azuma, Timothy Hla and Hajime Sano^*

^* Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Oral and Maxillofacial Surgery 2, Tokushima University School of Density, Tokushima, Japan; and Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030

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 S1P₁ have been implicated in many critical cellular events including inflammation, cancer, and angiogenesis. This study was undertaken to examine the role of S1P₁ signaling in the pathogenesis of primary SS. S1P₁ 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 S1P₁ in inflammatory mononuclear cells was enhanced in advanced stages of primary SS. S1P enhanced proliferation and IFN- production by CD4⁺ T cells. The enhancing effect of S1P on IFN- 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- 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 S1P₁ signaling may modulate the autoimmune phenotype of primary SS by the action of immune as well as epithelial cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant-in-Aid 17659306 for Exploratory Research from the Ministry of Education, Science and Culture of Japan.

² Address correspondence and reprint requests to Dr. Tsuyoshi Iwasaki, Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. E-mail address: tsuyo-i{at}hyo-med.ac.jp

³ Abbreviations used in this paper: SS, Sjögren’s syndrome; LSG, labial salivary gland; PTX, pertussis toxin; S1P, sphingosine 1-phosphate; SK, sphingosine kinase; GPCR, G protein-coupled receptor.