Abstract
Schistosomiasis is characterized by egg deposition, granulomatous inflammatory reaction and then subsequent hepatic fibrosis formation. Activated HSCs are regarded as the main effector cells in the progression of liver fibrosis and induction of senescence in hepatic stellate cells (HSCs) is vital to the reversion of hepatic fibrosis. Our previous work has showed that S. japonicum egg antigen p40 (Sjp40) could promote HSCs senescence via a STAT3/p53/p21 mechanism. In this paper, the major aim was to explore whether there are other signaling pathways in the process of Sjp40-induced HSCs aging and the underlying effect of SKP2/P27 signal pathway in this procedure. We observed the Sjp40-induced decrease of α-SMA and the senescence of LX-2 cells, and Sjp40 could upregulate P27 and downregulate the protein level of SKP2. The senescence induced by Sjp40 might be reversed in LX-2 cells that treated with P27-specific siRNA or with SKP2-special over-expression plasmid. In addition, we also demonstrated that the decreased expression of P-Rb and α-SMA induced by Sjp40 were partly restored by SKP2-overexpression. These data suggest that Sjp40 might inhibit HSCs activation by promoting cellular senescence via SKP2/P27 signaling pathway, which put forward novel mechanism in the treatment of liver fibrosis.
Highlights
Schistosomiasis is one of the most important causes of liver fibrosis, which is characterized by egg deposition, granulomatous inflammatory reaction and subsequent hepatic fibrosis formation[7, 8]
Some studies have demonstrated that IL-10 could regress liver fibrosis via suppressing expression of matrix metalloproteinase and collagen[16, 17], while IL-5 promoted the progression of hepatic fibrosis by the regulation of IL-13 activity[18]
It is well known that the activation of hepatic stellate cells (HSCs) plays a key role in liver fibrogenesis, and activated HSCs are the main source of ECM and characterized by the expression of α-SMA2
Summary
Schistosomiasis is one of the most important causes of liver fibrosis, which is characterized by egg deposition, granulomatous inflammatory reaction and subsequent hepatic fibrosis formation[7, 8]. Some studies have demonstrated that IL-10 could regress liver fibrosis via suppressing expression of matrix metalloproteinase and collagen[16, 17], while IL-5 promoted the progression of hepatic fibrosis by the regulation of IL-13 activity[18]. We have demonstrated that Sjp[40] could promote HSCs senescence via a STAT3/p53/p21 dependent mechanism[21]. This signal pathway interference could not completely rescue the Sjp40-induced senescence. In this present paper we attempted to explore the role of SKP2/P27 pathway in Sjp40-induced HSCs senescence and elucidate the underlying molecular mechanism
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