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

Abstract

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 S1P 3 receptor expression in liver tissue were markedly up-regulated in a mouse model of cholestasis-induced liver fibrosis. In addition, the S1P 3 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 S1P 3 expression significantly inhibited S1P-induced BM cell migration in vitro. Furthermore, a selective S1P 3 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 ␣-actin expression, and decreased total hydroxyproline content. In conclusion, our data suggest that S1P/S1P 3 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

Suramin Inhibits the Development and Progression of Peritoneal Fibrosis

“…Mechanistic studies demonstrate that suramin inhibits apoptosis, suppresses expression of proinflammatory cytokines, inactivates myofibroblasts, and blocks multiple cell signaling pathways . Recent animal studies from our laboratory and by other investigators have shown that administration of suramin can attenuate muscle, liver, and renal fibrosis (Chan et al, 2003;Li et al, 2009;. We have shown that suramin treatment can suppress the expression of fibronectin and a-SMA and type I collagen and reduce the deposition of extracellular matrix (ECM).…”

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

“…Therefore, the inhibition of those receptors may account, at least in part, for the antifibrotic effect of suramin observed after UUO injury. Nevertheless, suramin is an inhibitor with broad specificity and also inhibits other membrane receptors such as purinergic receptor P2X 7 and sphingosine-1-phosphate receptors (Goncalves et al, 2006;Li et al, 2009). Because these two receptors are also associated with development and progression of tissue fibrosis, it will be interesting to further investigate whether blockade of these receptors by suramin contributes to its antifibrotic effects.…”

“…Studies on animal models have shown that administration of suramin attenuates muscle and liver fibrosis (Chan et al, 2003;Li et al, 2009). Furthermore, suramin can prevent coronary restenosis after percutaneous transluminal coronary angioplasty (Urasawa et al, 2001).…”

Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

“…Suramin is also a potent inhibitor for purinergic receptors and sphingosine-1-phosphate receptors. 34,43 Recent studies have shown that the development of renal fibrosis after UUO injury and of hepatic fibrosis after bile duct ligation is associated with P2X 7 and sphingosine-1-phosphate receptors. 44,45 Further investigations are needed to evaluate whether the antifibrotic action of suramin is also associated with inhibition of these two receptors in the kidney.…”

“…31,32 Recent experimental studies showed that it is also effective in attenuating muscle and liver fibrosis. 33,34 However, it remains unclear whether suramin has an antifibrotic effect in the kidney.…”