Interleukin-10 induces senescence of activated hepatic stellate cells via STAT3-p53 pathway to attenuate liver fibrosis
Interleukin-10 induces senescence of activated hepatic stellate cells via STAT3-p53 pathway to attenuate liver fibrosis
复制标题
Interleukin-10 通过 STAT3-p53 途径诱导激活的肝星状细胞衰老，从而减轻肝纤维化
DOI：
10.1016/j.cellsig.2019.109445
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发表时间：
2020-02-01
影响因子：
4.8
通讯作者：
Wang, Xiao-Zhong
中科院分区：
文献类型：
--
作者：
Huang, Yue-Hong;Chen, Ming-Hua;Wang, Xiao-Zhong
肝纤维化是一种创伤愈合过程，其导致响应于各种肝损伤的过量异常细胞外基质（ECM）沉积。活化的肝星状细胞（HSC）是ECM的主要来源，诱导活化的HSC衰老是肝纤维化的一种有吸引力的治疗策略。我们前期的研究表明，白细胞介素-10（IL-10）对四氯化碳（CCL 4）和猪血清诱导的大鼠肝纤维化有明显的抑制作用。然而，关于IL-10调节活化的HSC衰老的机制知之甚少。本研究的目的是揭示IL-10介导活化的HSC衰老以减轻肝纤维化的潜在途径。在体内，我们发现IL-10基因通过基于流体动力学的转染减轻了CCL 4诱导的大鼠肝纤维化与活化的HSC的衰老相关。体外实验证实，IL-10可通过抑制细胞增殖、诱导细胞周期阻滞、提高SA-β-Gal活性、增强衰老标志蛋白p53和p21的表达等途径诱导活化的HSC衰老。用Pifithrin-alpha（一种p53的特异性抑制剂）处理可以消除活化的HSC中IL-10增加的SA-β-Gal活性以及P53和P21的表达。最后，IL-10还增加了总的和磷酸化的信号转导子和转录激活子3（STAT 3）的表达，并促进磷酸化的STAT 3从细胞质向细胞核的移位。STAT 3特异性抑制剂隐丹参酮可抑制IL-10诱导的活化HSC中STAT 3磷酸化及其下游蛋白p53和p21的表达，降低SA-β-Gal活性。综上所述，IL-10通过STAT 3-p53途径诱导活化的HSC衰老，减轻大鼠肝纤维化，本研究为IL-10抗肝纤维化作用提供了新的机制。
Hepatic fibrosis is a wound healing process which results in deposition of excessive abnormal extracellular matrix (ECM) in response to various liver injuries. Activated hepatic stellate cells (HSCs) are the major sources of ECM and induction of senescence of activated HSCs is an attractive therapeutic strategy for liver fibrosis. Our previous studies have shown that interleukin-10 (IL-10) attenuates the carbon tetrachloride (CCL4) - and porcine serum-induced liver fibrosis in rats. However, little is known about the mechanisms of IL-10 regulating the senescence of activated HSCs. The aim of this study is to uncover the underlying pathway by which IL-10 mediates activated HSCs senescence to attenuate liver fibrosis. In vivo, we found that IL-10 gene by hydrodynamics-based transfection attenuated CCL4-induced liver fibrosis associated with senescence of activated HSCs in rats. In vitro experiment confirmed that IL-10 could induce senescence of activated HSCs via inhibiting cell proliferation, inducing cell cycle arrest, increasing the SA-beta-Gal activity and enhancing expression of senescence marker protein p53 and p21. Treatment with Pifithrin-alpha, a specific inhibitor of p53, could abrogate IL-10-increased SA-beta-Gal activity and expression of P53 and P21 in activated HSCs. Lastly, IL-10 also increased the expression of total and phosphorylated signal transducers and activators of transcription 3(STAT3) and promoted phosphorylated STAT3 translocation from cytoplasm to nucleus. Treatment with cryptotanshinone, a specific inhibitor of STAT3, could inhibit the phosphorylation of STAT3 and its downstream proteins p53 and p21 expression and decrease the activity of SA-beta-Gal in activated HSCs induced by IL-10. Taken together, IL-10 induced senescence of activated HSCs via STAT3-p53 pathway to attenuate liver fibrosis in rats and present study will provide a new mechanism of antifibrotic effects of IL-10.