Involvement of Sphingosine 1-Phosphate (SIP)/S1P3 Signaling in Cholestasis-Induced Liver Fibrosis

Bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) have been implicated in many critical cellular events, including inflammation, cancer, and angiogenesis. However, the role of S1P/S1PR signaling in the pathogenesis of liver fibrosis has not been well documented. In this study, we found that S1P levels and S1P3 receptor expression in liver tissue were markedly up-regulated in a mouse model of cholestasis-induced liver fibrosis. In addition, the S1P3 receptor was also expressed in green fluorescent protein transgenic bone marrow (BM)-derived cells found in the damaged liver of transplanted chimeric mice that underwent bile duct ligation. Silencing of S1P3 expression significantly inhibited S1P-induced BM cell migration in vitro. Furthermore, a selective S1P3 receptor antagonist, suramin, markedly reduced the number of BM-derived cells during cholestasis. Interestingly, suramin administration clearly ameliorated bile duct ligation-induced hepatic fibrosis, as demonstrated by attenuated deposition of collagen type I and III, reduced smooth muscle α-actin expression, and decreased total hydroxyproline content. In conclusion, our data suggest that S1P/S1P3 signaling plays an important role in cholestasis-induced liver fibrosis through mediating the homing of BM cells. Modulation of S1PR activity may therefore represent a new antifibrotic strategy.