Abstract
Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) system has been implicated in the pathological process of liver injury. This study was designed to evaluate the effects of S1P/S1PR on bone marrow-derived monocyte/macrophage (BMM) migration in mouse models of cholestatic liver injury, and identify the signaling pathway underlying this process. S1PR1-3 expression in BMM was characterized by immunofluorescence, RT-PCR and Western blot. Cell migration was determined in Boyden chambers. In vivo, the chimera mice, which received BM transplants from EGFP-transgenic mice, received an operation of bile duct ligation (BDL) to induce liver injury with the administration of S1PR2/3 antagonists. The results showed that S1PR1-3 were all expressed in BMMs. S1P exerted a powerful migratory action on BMMs via S1PR2 and S1PR3. Furthermore, PTX and LY-294002 (PI3K inhibitor) prevented S1PR2/3-mediated BMM migration, and Rac1 activation by S1P was inhibited by JTE-013, CAY-10444 or LY294002. Administration of S1PR2/3 antagonists in vivo significantly reduced BMM recruitment in BDL-treated mice, and attenuated hepatic inflammation and fibrosis. In conclusion, S1P/S1PR2/3 system mediates BMM motility by PTX-PI3K-Rac1 signaling pathway, which provides new compelling information on the role of S1P/S1PR in liver injury and opens new perspectives for the pharmacological treatment of hepatic fibrosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / cytology*
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Cell Movement / drug effects
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Cells, Cultured
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Chemokines / analysis
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Chemokines / genetics
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Chromones / pharmacology
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Cytokines / analysis
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Cytokines / genetics
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Enzyme-Linked Immunosorbent Assay
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Fatty Liver / metabolism
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Fatty Liver / pathology
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Fibrosis
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Liver / metabolism
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Liver / pathology
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Lysophospholipids / metabolism
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Macrophages / cytology
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Macrophages / metabolism*
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Mice
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Mice, Inbred ICR
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Mice, Transgenic
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Microscopy, Fluorescence
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Morpholines / pharmacology
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Neuropeptides / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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RNA Interference
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RNA, Small Interfering / metabolism
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Real-Time Polymerase Chain Reaction
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Receptors, Lysosphingolipid / antagonists & inhibitors
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / metabolism*
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Signal Transduction / drug effects
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Sphingosine / analogs & derivatives
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Sphingosine / metabolism
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Sphingosine-1-Phosphate Receptors
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rac1 GTP-Binding Protein / metabolism
Substances
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Chemokines
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Chromones
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Cytokines
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JTE 013
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Lysophospholipids
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Morpholines
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Neuropeptides
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Phosphoinositide-3 Kinase Inhibitors
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Pyrazoles
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Pyridines
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RNA, Small Interfering
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Rac1 protein, mouse
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Receptors, Lysosphingolipid
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S1PR3 protein, rat
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S1pr1 protein, mouse
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Sphingosine-1-Phosphate Receptors
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sphingosine-1-phosphate receptor-2, mouse
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sphingosine 1-phosphate
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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rac1 GTP-Binding Protein
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Sphingosine