Intracellular Sphingosine 1-Phosphate Contributes to Collagen Expression of Hepatic Myofibroblasts in Human Liver Fibrosis Independent of Its Receptors
Intracellular Sphingosine 1-Phosphate Contributes to Collagen Expression of Hepatic Myofibroblasts in Human Liver Fibrosis Independent of Its Receptors
复制标题
细胞内 1-磷酸鞘氨醇有助于人肝纤维化中肝肌成纤维细胞的胶原表达，与其受体无关
DOI：
10.1016/j.ajpath.2014.09.023
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发表时间：
2015-02-01
影响因子：
6
通讯作者：
Li, Liying
中科院分区：
文献类型：
--
作者：
Xiu, Lei;Chang, Na;Li, Liying
1-磷酸鞘氨醇（S1 P）参与多种病理过程，包括纤维化。S1 P通过旁分泌方式参与小鼠肝纤维化的形成。在此，我们研究了S1 P在人类肝纤维化中的参与。从接受肝移植的患者的肝脏获得人纤维化样品。通过免疫荧光、实时RT-PCR、高含量分析或蛋白质印迹分析来表征纤维化肝脏、人骨髓源性间充质干细胞和人肝原性促纤维化细胞中鞘氨醇激酶（SphK 1）、胶原（Col）alpha 1（I）、Col alpha 1（III）、α-平滑肌肌动蛋白和p-Smad 2/3的表达。使用siSphK 1或SphK特异性抑制剂评估SphK 1的作用。SphK 1在人纤维化肝肌成纤维细胞中表达，可在人骨髓来源的间充质干细胞或由转化生长因子01（TGF-β 1）激活的人肝原性纤维化细胞中检测到。TGF-β 1以TGF-13受体依赖性方式诱发SphK 1的活化，增加细胞内S1 P，并上调SphK 1、Col alpha 1（I）和Col al（III）的表达。TGF-131通过SphK 1诱导Col a1（1）和Col a1（III）的表达，这是由细胞内S1 P介导的，不依赖于S1 P受体。TGF-131以TGF-13受体依赖性而非SphK-1依赖性方式诱导p-Smad 2和p-Smad 3核转位。总之，细胞内S1 P在TGF-131诱导的Col α 1（I）和Col α 1（III）表达中起关键作用，这是人类纤维化发展所需的。S1 P的作用不依赖于S1 P受体。
Sphingosine 1-phosphate (S1P) is involved in multiple pathological processes, including fibrogenesis. S1P participates in mouse liver fibrogenesis via a paracrine manner. Herein, we investigated the involvement of S1P in human Liver fibrosis. Human fibrotic samples were obtained from livers of patients undergoing liver transplantation. Expression of sphingosine kinase (SphK1), collagen (Col) alpha 1(I), Col alpha 1(III), a-smooth muscle actin, and p-Smad2/3 was characterized by immunofluorescence, real-time RT-PCR, high-content analysis, or Western blot analysis in the fibrotic liver, human bone marrow derived mesenchymal stem cells, and human hepatogenic profibrotic cells. The effect of SphK1 was assessed using siSphK1 or SphK-specific inhibitor. SphK1, which was expressed in human fibrotic Liver myofibroblasts, could be detected in human bone marrow-derived mesenchymal stem cells or human hepatogenic profibrotic cells activated by transforming growth factor 01 (TGF-beta 1). TGF-beta 1 evoked the activation of SphK1, increased intracellular S1P, and up-regulated expression of SphK1, Col alpha 1(I), and Col al(III) in a TGF-13 receptor dependent manner. TGF-131 induced expression of Col a1(1) and Col a1(III) via SphK1, which was mediated by intracellular S1P, independent of S1P receptors. TGF-131 evoked nuclear transLocation of p-Smad2 and p-Smad3 in TGF-I3 receptor dependent, but SphK1-independent, manner. In conclusion, intracellular S1P plays a crucial role in the TGF-131 induced expression of Col oc1 (I) and Col a1 (III), which is required for human fibrosis development. S1P exerts its effects in S1P receptor independent manner.