Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility
Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility
复制标题
1-磷酸鞘氨醇 (S1P)/S1P 受体通过作用于肝肌成纤维细胞运动参与人肝纤维化
DOI：
10.1016/j.jhep.2010.08.028
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发表时间：
2011-06-01
影响因子：
25.7
通讯作者：
Li, Liying
中科院分区：
文献类型：
--
作者：
Li, Changyong;Zheng, Sujun;Li, Liying
背景与目的：肝肌成纤维细胞（hMFs）定向迁移参与肝纤维化的发生发展。然而，调节这些细胞运动性的信号还不完全清楚。我们最近发现，鞘氨醇1-磷酸（S1 P）和S1 P受体（S1 PRs）参与小鼠肝纤维化。在这里，我们研究了S1 P/S1 PRs信号在人肝纤维化中的作用，涉及人hMFs的运动。方法：采用高效液相色谱法检测肝脏中的SiP水平。通过免疫荧光和实时RT-PCR或Western印迹分析，在人肝活检标本和培养的hMFs中表征S1 PRs的表达。在Boyden室中测定细胞迁移，通过使用选择性S1 P受体激动剂或拮抗剂和沉默S1 PRs表达与小干扰RNA.Results：在人类纤维化肝脏中的SiP水平增加，通过上调鞘氨醇激酶（SphK），无论纤维化的病因。S1 P受体1型、2型和3型（S1 P（1，2，3））在体内和体外人hMFs中表达。有趣的是，S1 P（1，3）在人纤维化样品中被强烈诱导，而S1 P（2）的表达大量减少。S1 P对人hMFs具有很强的迁移作用。此外，SEW 2871（一种S1 P（1）激动剂）模拟了S1 P的作用，并被苏拉明（一种S1 P（3）拮抗剂）和沉默S1 P（1，3）表达所阻断。结论：SphK/S1 P/S1 PRs信号转导轴在人肝纤维化中起重要作用，并参与人hMFs向损伤区的定向迁移。(C)2010年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Directed migration of hepatic myofibroblasts (hMFs) contributes to the development of liver fibrosis. However, the signals regulating the motility of these cells are incompletely understood. We have recently shown that sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) are involved in mouse liver fibrogenesis. Here, we investigated the role of S1P/S1PRs signals in human liver fibrosis involving motility of human hMFs.Methods: Si P level in the liver was examined by high-performance liquid chromatography. Expression of S1PRs was characterized, in biopsy specimens of human liver and cultured hMFs, by immunofluorescence and real-time RT-PCR or Western blot analysis. Cell migration was determined in Boyden chambers, by using the selective S1P receptor agonist or antagonist and silencing of S1PRs expression with small interfering RNA.Results: Si P level in the human fibrotic liver was increased through up-regulation of sphingosine kinase (SphK), irrespective of the etiology of fibrosis. S1P receptors type 1, 2, and 3 (S1P(1,2,3)) were expressed in human hMFs in vivo and in vitro. Interestingly, S1P(1,3) were strongly induced in human fibrotic samples, whereas expression of S1P(2) was massively decreased. S1P exerted a powerful migratory action on human hMFs. Furthermore, the effect of S1P was mimicked by SEW2871 (an S1P(1) agonist), and blocked by suramin (an S1P(3) antagonist) and by silencing S1P(1,3) expression. In contrast, JTE-013 (an S1P(2) antagonist) and silencing of S1P(2) expression enhanced S1P-induced migration.Conclusions: SphK/S1P/S1PRs signaling axis plays an important role in human liver fibrosis and is involved in the directed migration of human hMFs into the damaged areas. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.