RSjp40 inhibits activated hepatic stellate cells by promoting nuclear translocation of YB1 and inducing BMP-7/Smad1/5/8 pathway

Liuting Chen,Ertao Liu,Lian Duan,Qi Zhou,Dandan Zhu,Jinling Chen,Jiali Zhang,Yinong Duan

doi:10.1186/s13071-019-3539-z

Liuting Chen, Ertao Liu + Show 6 more

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https://doi.org/10.1186/s13071-019-3539-z

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Abstract

BackgroundActivation of hepatic stellate cells is the dominant pathogenic event during the process of liver fibrosis. Bone morphogenic protein (BMP)-7 has recently been identified as an anti-fibrotic factor and leads to phosphorylation of Smad1/5/8 in activated hepatic stellate cells. Its expression can be upregulated by the transcriptional activator, Y-Box protein-1 (YB1). Previous studies have found that the recombinant Schistosoma japonicum protein p40 (rSjp40) can inhibit the activation of hepatic stellate cells, and based on this evidence we attempted to investigate whether or not BMP-7 is involved in rSjp40’s inhibition.MethodsA human hepatic stellate cell line, the LX-2 cell line, was cultured and treated with rSjp40. The role of BMP-7 was analyzed by Western blot.ResultsOur findings testified that knockdown of BMP-7 impaired rSjp40-induced downregulation of α-SMA and phosphorylation of Smad1/5/8 in LX-2 cells. Furthermore, rSjp40 upregulated expression of BMP-7 at both mRNA and protein levels depending on YB1. Interestingly, YB1 was translocated from the cytoplasm to the nucleus upon treatment of rSjp40.ConclusionsThese results suggest that rSjp40 inhibits the activation of hepatic stellate cells by promoting nuclear translocation of YB1 and inducing BMP-7/Smad1/5/8 pathway, which provide a new clue to guide ongoing research into the anti-fibrosis of rSjp40.

Highlights

Activation of hepatic stellate cells is the dominant pathogenic event during the process of liver fibrosis
We found that soluble egg antigens (SEA) from Schistosoma japonicum can induce the suppression of activated human stellate cell line, LX-2 cells and primary mouse hepatic stellate cell (HSC) through the transforming growth factor-β1 (TGF-β1) and PPARγ signaling pathways [18]
Knockdown of Bone morphogenic protein (BMP)-7 markedly inhibited recombinant Schistosoma japonicum protein p40 (rSjp40)-triggered phosphorylation of Smad1/5/8 in LX-2 cells (t-test: t(4) = 6.767, P = 0.0012) (Fig. 2). These results suggest that rSjp40 inhibits activation of HSCs partially via BMP-7/ Smad1/5/8-dependent mechanism

Summary

Introduction

Activation of hepatic stellate cells is the dominant pathogenic event during the process of liver fibrosis. Bone morphogenic protein (BMP)-7 has recently been identified as an anti-fibrotic factor and leads to phosphorylation of Smad1/5/8 in activated hepatic stellate cells. Liver fibrosis is a pathological process due to most chronic liver injuries like viral hepatitis, alcohol abuse, metabolic disease, and parasite infection. Both quantitative and qualitative changes in the composition of liver extracellular matrix (ECM) occur during the development of liver fibrosis. Bone morphogenic protein (BMP)-7, a member of the TGF-β superfamily, has been reported to counteract some of the profibrogenic actions of TGF-β1 [5] It initiates the signal transduction cascade by allowing phosphorylation of Smad1/5/8. In the Schistosoma japonicum-induced liver fibrosis mouse model, administration of recombinant BMP-7 intraperitoneally significantly decreased the degree of collagen deposition and the expression of α-SMA in the liver, measured by Masson’s staining and α-SMA staining [12]

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