Sphingosine 1‐phosphate has anti‐apoptotic effect on liver sinusoidal endothelial cells and proliferative effect on hepatocytes in a paracrine manner in human

<jats:sec><jats:title>Aim</jats:title><jats:p>Sphingosine 1‐phosphate (<jats:styled-content style="fixed-case">S1P</jats:styled-content>) is a bioactive sphingolipid metabolite released from erythrocytes and platelets, and is a potent stimulus for endothelial cell proliferation. However, the role of <jats:styled-content style="fixed-case">S1P</jats:styled-content> on human liver sinusoidal endothelial cells (<jats:styled-content style="fixed-case">LSEC</jats:styled-content>) remains unclear. The proliferation and inhibition of apoptosis in <jats:styled-content style="fixed-case">LSEC</jats:styled-content> are involved in the promotion of liver regeneration and the suppression of liver injury after liver resection and transplantation. The aim of this study is to investigate the role of <jats:styled-content style="fixed-case">S1P</jats:styled-content> on human <jats:styled-content style="fixed-case">LSEC</jats:styled-content> and the interaction between <jats:styled-content style="fixed-case">S1P</jats:styled-content> and <jats:styled-content style="fixed-case">LSEC</jats:styled-content> in hepatocyte proliferation <jats:italic>in vitro</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Immortalized human <jats:styled-content style="fixed-case">LSEC</jats:styled-content> were used. <jats:styled-content style="fixed-case">LSEC</jats:styled-content> were cultured with <jats:styled-content style="fixed-case">S1P</jats:styled-content>, and the cell proliferation, anti‐apoptosis, signal transductions and production of cytokines and growth factors were subsequently examined. To investigate the interaction between <jats:styled-content style="fixed-case">S1P</jats:styled-content> and <jats:styled-content style="fixed-case">LSEC</jats:styled-content> in hepatocyte proliferation, primary human hepatocytes were cultured with the supernatants of <jats:styled-content style="fixed-case">LSEC</jats:styled-content> with and without <jats:styled-content style="fixed-case">S1P</jats:styled-content>. <jats:styled-content style="fixed-case">DNA</jats:styled-content> synthesis and signal transductions in hepatocytes were examined.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:styled-content style="fixed-case">S1P</jats:styled-content> induced <jats:styled-content style="fixed-case">LSEC</jats:styled-content> proliferation through activation of <jats:styled-content style="fixed-case">A</jats:styled-content>kt and extracellular signal‐related kinase pathways and suppressed <jats:styled-content style="fixed-case">LSEC</jats:styled-content> apoptosis by affecting the expression levels of <jats:styled-content style="fixed-case">B</jats:styled-content>cl‐2, <jats:styled-content style="fixed-case">B</jats:styled-content>ax and cleaved caspase‐3. <jats:styled-content style="fixed-case">S1P</jats:styled-content> promoted interleukin‐6 (<jats:styled-content style="fixed-case">IL</jats:styled-content>‐6) and vascular endothelial growth factor (<jats:styled-content style="fixed-case">VEGF</jats:styled-content>) production in <jats:styled-content style="fixed-case">LSEC</jats:styled-content>. The supernatants of <jats:styled-content style="fixed-case">LSEC</jats:styled-content> cultured with <jats:styled-content style="fixed-case">S1P</jats:styled-content> enhanced hepatocyte <jats:styled-content style="fixed-case">DNA</jats:styled-content> synthesis more strongly than the supernatants of <jats:styled-content style="fixed-case">LSEC</jats:styled-content> cultured without <jats:styled-content style="fixed-case">S1P</jats:styled-content> through activation of the signal transducer and activator of transcription‐3 pathway.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p><jats:styled-content style="fixed-case">S1P</jats:styled-content> has proliferative and anti‐apoptotic effects and promotes the production of <jats:styled-content style="fixed-case">IL</jats:styled-content>‐6 and <jats:styled-content style="fixed-case">VEGF</jats:styled-content> in human <jats:styled-content style="fixed-case">LSEC</jats:styled-content>, thereby promoting hepatocyte proliferation.</jats:p></jats:sec>