Role of sphingosine 1-phosphate in the pathogenesis of Sjogren's syndrome
Role of sphingosine 1-phosphate in the pathogenesis of Sjogren's syndrome
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DOI：
10.4049/jimmunol.180.3.1921
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发表时间：
2008-02-01
影响因子：
4.4
通讯作者：
Sano, Hajime
中科院分区：
文献类型：
--
作者：
Sekiguchi, Masahiro;Iwasaki, Tsuyoshi;Sano, Hajime
原发性干燥综合征（SS）是一种以炎性单核细胞浸润和泪腺及唾液腺上皮细胞破坏为特征的自身免疫性疾病。1-磷酸鞘氨醇（S1 P）及其受体S1 P（1）的信号转导与许多关键的细胞事件有关，包括炎症、癌症和血管生成。本研究旨在探讨S1 P（1）信号在原发性SS发病机制中的作用。通过免疫组织化学方法，在所有唇侧唾液腺的炎症单核细胞、血管内皮细胞和上皮细胞的胞浆中检测到S1 P（1）和将鞘氨醇转化为S1 P（1）的鞘氨醇激酶1。S1 P（1）在炎症单核细胞中的表达在原发性SS的晚期增强。S1 P增强CD 4（+）T细胞的增殖和IFN-γ的产生。与健康对照组相比，原发性SS患者中S1 P对CD 4（+）T细胞产生IFN-γ的增强作用更强。S1 P还增强了唾液腺上皮细胞Fas表达和Fas介导的caspase-3诱导。IL-6在炎症单核细胞和导管上皮细胞的胞浆中表达，并在原发性SS的晚期增强。此外，IFN-γ和S1 P均增强唾液腺上皮细胞分泌IL-6。百日咳毒素预处理可抑制S1 P的上述作用。我们的数据显示，S1 P（1）信号可能通过免疫细胞和上皮细胞的作用调节原发性SS的自身免疫表型。
Primary Sjogren'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(1) 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.