sphingosine-1-phosphate and Sjogren-s-Syndrome

Sphingosine-1-phosphate (S1P) is a significant lipid messenger modulating many physiological responses. S1P plays a critical role in autoimmune disease and is suggested to be involved in Sjögren's syndrome pathology. However, the mechanism of S1P signaling in salivary glands is unclear. Here we studied the effects of S1P on normal human submandibular gland cells. S1P increased levels of the intracellular Ca(2+) concentration ([Ca(2+)](i)), which was inhibited by pre-treatment with U73122 or 2-aminoethoxydiphenyl borate (2-APB). Pre-treated S1P did not inhibit subsequent carbachol-induced [Ca(2+)](i) increase, which suggests that S1P and muscarinic signaling are independent of each other. S1P1, S1P2, and S1P3 receptors SphK1 and SphK2 were commonly expressed in human salivary gland cells. S1P, but not carbachol, induces the expression of interleukin-6 and Fas. Our results suggest that S1P triggers Ca(2+) signaling and the apoptotic pathway in normal submandibular gland cells, which suggests in turn that S1P affects the progression of Sjögren's syndrome.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Boron Compounds; Calcium Signaling; Carbachol; Cell Culture Techniques; Cells, Cultured; Cholinergic Agonists; Estrenes; fas Receptor; Female; Humans; Interleukin-6; Lysophospholipids; Male; Middle Aged; Phosphodiesterase Inhibitors; Phosphotransferases (Alcohol Group Acceptor); Pyrrolidinones; Receptors, Lysosphingolipid; Signal Transduction; Sjogren's Syndrome; Sphingosine; Submandibular Gland; Type C Phospholipases

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.

Topics: Adult; Autoimmune Diseases; Caspase 3; CD4-Positive T-Lymphocytes; Dendritic Cells; Epithelial Cells; fas Receptor; Female; Humans; Interferon-gamma; Interleukin-6; Lymphocyte Activation; Lysophospholipids; Male; Middle Aged; Receptors, Lysosphingolipid; RNA, Messenger; Salivary Glands; Sjogren's Syndrome; Sphingosine