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【Blood】1-磷酸鞘氨醇通过激发S1P1/Gi/PLC/Ca2+ 信号
Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways
Chang Min Yoon1, Bok Sil Hong1, Hyung Geun Moon1, Seyoung Lim1, Pann-Ghill Suh1, Yoon-Keun Kim1, Chi-Bom Chae2, and Yong Song Gho1
1 Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea; and 2 Institute of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea
The lymphatic system plays pivotal roles in mediating tissue fluid homeostasis and immunity, and excessive lymphatic vessel formation is implicated in many pathological conditions, which include inflammation and tumor metastasis. However, the molecular mechanisms that regulate lymphatic vessel formation remain poorly characterized. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that is implicated in a variety of biologic processes such as inflammatory responses and angiogenesis. Here, we first report that S1P acts as a lymphangiogenic mediator. S1P induced migration, capillary-like tube formation, and intracellular Ca2+ mobilization, but not proliferation, in human lymphatic endothelial cells (HLECs) in vitro. Moreover, a Matrigel plug assay demonstrated that S1P promoted the outgrowth of new lymphatic vessels in vivo. HLECs expressed S1P1 and S1P3, and both RNA interference–mediated down-regulation of S1P1 and an S1P1 antagonist significantly blocked S1P-mediated lymphangiogenesis. Furthermore, pertussis toxin, U73122 [GenBank] , and BAPTA-AM efficiently blocked S1P-induced in vitro lymphangiogenesis and intracellular Ca2+ mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/Gi/phospholipase C/Ca2+ signaling pathways. Our results suggest that S1P is the first lymphangiogenic bioactive lipid to be identified, and that S1P and its receptors might serve as new therapeutic targets against inflammatory diseases and lymphatic metastasis in tumors. Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways
鞘氨醇- 1 -磷酸盐通过激发s1p1/gi/plc/ca2 +信号转导途径促进淋巴管生成
Chang Min Yoon1, Bok Sil Hong1, Hyung Geun Moon1, Seyoung Lim1, Pann-Ghill Suh1, Yoon-Keun Kim1, Chi-Bom Chae2, and Yong Song Gho1
Chang Min Yoon1, Bok Sil Hong1, Hyung Geun Moon1, Seyoung Lim1, Pann-Ghill Suh1, Yoon-Keun Kim1, Chi-Bom Chae2, and Yong Song Gho1
1 Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea; and 2 Institute of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea
1分工分子和生命科学，浦项科技大学，浦项，韩国;2生物医学科学和技术研究所，建国大学，汉城，韩国
The lymphatic system plays pivotal roles in mediating tissue fluid homeostasis and immunity, and excessive lymphatic vessel formation is implicated in many pathological conditions, which include inflammation and tumor metastasis. However, the molecular mechanisms that regulate lymphatic vessel formation remain poorly characterized. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that is implicated in a variety of biologic processes such as inflammatory responses and angiogenesis. Here, we first report that S1P acts as a lymphangiogenic mediator. S1P induced migration, capillary-like tube formation, and intracellular Ca2+ mobilization, but not proliferation, in human lymphatic endothelial cells (HLECs) in vitro. Moreover, a Matrigel plug assay demonstrated that S1P promoted the outgrowth of new lymphatic vessels in vivo. HLECs expressed S1P1 and S1P3, and both RNA interference–mediated down-regulation of S1P1 and an S1P1 antagonist significantly blocked S1P-mediated lymphangiogenesis. Furthermore, pertussis toxin, U73122 [GenBank] , and BAPTA-AM efficiently blocked S1P-induced in vitro lymphangiogenesis and intracellular Ca2+ mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/Gi/phospholipase C/Ca2+ signaling pathways. Our results suggest that S1P is the first lymphangiogenic bioactive lipid to be identified, and that S1P and its receptors might serve as new therapeutic targets against inflammatory diseases and lymphatic metastasis in tumors.
淋巴系统在调解组织液稳态和免疫力中发挥关键作用，过多的淋巴管的形成与在许多病理状态有关，其中包括炎症和肿瘤转移。然而，调节淋巴管生成的分子机制仍不清楚。鞘氨醇- 1 -磷酸盐（ s1p ）是参与多种生物学过程，如炎症反应和血管生成的一种强力的生物活性脂质。这里，我们首次报告指出， s1p作为一个淋巴管生成的调节基质。在在体外人类淋巴管内皮细胞（ hlecs ）， s1p诱导迁移，毛细管样管的形成，和细胞内钙代谢，而不是增值。此外， 基质胶堵塞检测表明， s1p促进体内新的淋巴管的外向生长。 hlecs表达s1p1和s1p3 ，RNA干涉介导的s1p1下调和1 s1p1拮抗剂都明显阻断了s1p介导的淋巴管的生成。此外，百日咳毒素， u73122 [GenBank] ，和BAPTA-AM 有效地阻止s1p诱导的体外淋巴管生成及hlecs细胞内钙的代谢 ，表明s1p通过刺激s1p1/Gi/phospholipase c/ca2 +信号转导途径促进淋巴管生成。我们的结果表明， s1p是有待确定的第一个淋巴管生成的生物活性脂质，并s1p及其受体可作为对炎症性疾病及淋巴结转移的肿瘤的新治疗目标。 鞘氨醇- 1 -磷酸盐通过激发s1p1/gi/plc/ca2 +信号转导途径促进淋巴管生成
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作者:admin@医学,生命科学 2011-09-19 05:11
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