Abstract
Sphingosine-l-phosphate (SIP) is a bioactive sphingolipid metabolite of ceramide produced by phosphorylation of sphingosine by sphingosine kinases (SphK) type 1 and 2. We previously identified SIP receptors (S1P1, S1P2 and S1P3) in human hepatic myofibroblasts. In the present study, we investigated the role of SIP receptors in the wound healing response elicited by acute toxic liver injury. Acute liver injury was induced by a single i.p. injection of carbon tetrachloride (CC14) in wild type (WT), S1P2 / and S1P3 / mice. Matrix remodelling was evaluated 72 hrs after CC14 injection by quantification of liver 0~-smooth muscle actin (0~SMA), TGF-[3, PDGE TIMP-1, collagen I and III mRNAs. Culture experiments were conducted in hepatic myofibroblasts isolated from WT and S1P2 / mice. The expression of S1P2, S1P3, SphK1 and SphK2 mRNAs was strongly increased following CC14 treatment, suggesting an involvement of the SIP system in the wound healing response; expression of S1P1 was unaffected by CC14 treatment. Induction of c~SMA mRNA and protein were markedly decreased in S1P2 / mice. In addition, induction of TGF-[3, PDGF-BB and TIMP-1 mRNAs were significantly lower in S1P2 / mice, whereas up-regulation of collagen I and III mRNAs was similar in both groups of animals. In contrast, 0~SMA and TGF-[3 mRNAs were similarly induced in WT and S1P3 / mice. S 1P dose-dependently stimulated DNA synthesis in hepatic myofibroblasts from WT mice and PDGF-BB enhanced the mitogenic effect of SIR In keeping with these findings, PDGF-BB strongly induced the expression of S1P2. In contrast, in hepatic myofibroblasts isolated from S1P2 / mice, there was a marked reduction of the mitogenic and comitogenic effects of SIR These results demonstrate that PDGF-BB potentiates the mitogenic effect of SIP, by a mechanism involving up-regulation of S1P2 expression. In conclusion, S1P2 knock-out mice show a reduced wound healing response, by a mechanism involving reduced proliferation of hepatic myofibroblasts. These results point out a novel role of S1P2 in matrix remodelling and suggest that S1P2 may promote liver fibrogenesis during chronic liver injury.
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