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Essential roles of sphingosine 1-phosphate receptor types 1 and 3 in human hepatic stellate cells motility and activation

Authors

  • Xihong Liu,

    1. Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
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  • Shi Yue,

    1. Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
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  • Changyong Li,

    1. Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
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  • Lin Yang,

    1. Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
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  • Hong You,

    1. Beijing Digestive Diseases Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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  • Liying Li

    Corresponding author
    1. Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
    • No.10 Xitoutiao, You An Men, Beijing 100069, PR China.
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  • Xihong Liu and Shi Yue contributed equally to this work.

Abstract

The biological roles of sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) have been broadly investigated. However, at present pathophysiological roles of S1P/S1PRs axis in liver fibrosis are not well defined. Here, we investigated the functions of S1P/S1PRs axis in human hepatic stellate cells (HSC) line, LX-2 cells. We found that S1PR types 1, 2 and 3 (S1PR1–3) are clearly detected in LX-2 cells, as determined by RT-PCR, Western blot and immunocytochemistry analysis. S1P exerted a powerful migratory action on LX-2 cells, as determined in Boyden chambers, and stimulated fibrogenic activity of LX-2 cells, as demonstrated by increase of expression of smooth muscle α-actin, procollagen α1(I) and α1(III) and total hydroxyproline content. Moreover, the effects of S1P were mimicked by S1PR1 agonist SEW2871, and abrogated by W146 (S1PR1 antagonist) and/or silencing S1PR1, three expression with small interfering RNA, suggesting the main roles of S1PR1 and 3. However, studies with S1PR2 antagonist JTE-013 and silencing S1PR2 expression indicated that S1PR2 negatively regulated S1P-induced cell migration. Interestingly, exogenously added S1P induced significant up-regulation of sphingosine kinase-1 and the synthesis of additional S1P, and expression of S1PR1,3, but not S1PR2. In conclusion, our data have identified an additional function regulated by S1P/S1PR1,3 axis involving migration and fibrogenic activation of HSCs. These results suggest that selective modulation of S1PR activity may represent a new antifibrotic strategy. J. Cell. Physiol. 226: 2370–2377, 2011. © 2010 Wiley-Liss, Inc.

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