Soluble egg antigens of Schistosoma japonicum induce senescence in activated hepatic stellate cells by activation of the STAT3/p53/p21 pathway.
Soluble egg antigens of Schistosoma japonicum induce senescence in activated hepatic stellate cells by activation of the STAT3/p53/p21 pathway.
复制标题
日本血吸虫可溶性卵抗原通过激活 STAT3/p53/p21 途径诱导激活的肝星状细胞衰老
DOI：
10.1038/srep30957
复制
发表时间：
2016-08-04
影响因子：
4.6
通讯作者：
Duan Y
中科院分区：
文献类型：
--
作者：
Chen J;Pan J;Wang J;Song K;Zhu D;Huang C;Duan Y
肝纤维化以肝星状细胞(HSCs)活化为特征。最近的研究结果表明，活化的HSCs的衰老可能限制了肝纤维化的发展。根据先前观察到的日本血吸虫虫卵抗原的体外抗纤维化作用，我们推测SEA可能通过促进活化的HSCs的衰老而起到缓解肝纤维化的重要作用。我们发现SEA在体外抑制了α-SMA和I型前胶原的表达，促进了活化的HSC的衰老。此外，SEA还诱导了P-p53和p21的表达增加。P53基因敲除可抑制p21的表达，但不能诱导活化的HSCs衰老。在SEA刺激下，STAT3的磷酸化水平升高，而STAT3的缺失则降低了P53的水平和HSCs的衰老。免疫沉淀分析结果表明，SOCS3可能通过与P53的相互作用参与SEA诱导的HSCs衰老。本研究证实了SEA通过促进HSCs衰老而抑制肝纤维化的潜在能力。此外，一条新的STAT3-P53-p21通路可能参与了SEA介导的HSCs衰老。我们的结果提示SEA可能通过促进衰老来抑制肝纤维化。
Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. Based on previously observed anti-fibrotic effects of soluble egg antigens from Schistosoma japonicum in vitro, we hypothesized that SEA might play a crucial role in alleviating liver fibrosis through promoting senescence of activated HSCs. We show here that SEA inhibited expression of α-SMA and pro-collagen I and promoted senescence of activated HSCs in vitro. In addition, SEA induced an increased expression of P-p53 and p21. Knockdown of p53 inhibited the expression of p21 and failed to induce senescence of activated-HSCs. Phosphorylated STAT3 was elevated upon SEA stimulation, while loss of STAT3 decreased the level of p53 and senescence of HSCs. Results from immunoprecipitation analysis demonstrated that SOCS3 might be involved in the SEA-induced senescence in HSCs through its interaction with p53. This study demonstrates the potential capacity of SEA in restricting liver fibrosis through promoting senescence in HSCs. Furthermore, a novel STAT3-p53-p21 pathway might participate in the observed SEA-mediated senescence of HSCs. Our results suggest that SEA might carry potential therapeutic effects of restraining liver fibrosis through promoting senescence.