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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

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Background6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients.MethodsA total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated.ResultsThe minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377–9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764–33.514, P = 3.75 × 10− 4). No differences were found between 6-MP dose intensity and ITPA polymorphisms.ConclusionNUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.