Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, China.
Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou 350001, China.
Exp Biol Med (Maywood). 2021 Feb;246(4):447-458. doi: 10.1177/1535370220960391. Epub 2020 Oct 7.
Activated hepatic stellate cells are reported to play a significant role in liver fibrogenesis. Beside the phenotype reversion and apoptosis of activated hepatic stellate cells, the senescence of activated hepatic stellate cells limits liver fibrosis. Our previous researches have demonstrated that interleukin-10 could promote hepatic stellate cells senescence via p53 signaling pathway However, the relationship between expression of p53 and senescence of activated hepatic stellate cells induced by interleukin-10 in fibrotic liver is unclear. The purpose of present study was to explore whether p53 plays a crucial role in the senescence of activated hepatic stellate cells and degradation of collagen mediated by interleukin-10. Hepatic fibrosis animal model was induced by carbon tetrachloride through intraperitoneal injection and transfection of interleukin-10 gene to liver was performed by hydrodynamic-based transfer system. Depletions of p53 and were carried out by adenovirus-based short hairpin RNA against p53. Regression of fibrosis was assessed by liver biopsy and collagen staining. Cellular senescence in the liver was observed by senescence-associated beta-galactosidase (SA-β-Gal) staining. Immunohistochemistry, immunofluorescence double staining, and Western blot analysis were used to evaluate the senescent cell and senescence-related protein expression. Our data showed that interleukin-10 gene treatment could lighten hepatic fibrosis induced by carbon tetrachloride and induce the aging of activated hepatic stellate cells accompanied by up-regulating the expression of aging-related proteins. We further demonstrated that depletion of p53 could abrogate up-regulation of interleukin-10 on the expression of senescence-related protein and . Moreover, p53 knockout in fibrotic mice could block not only the senescence of activated hepatic stellate cells, but also the degradation of fibrosis induced by interleukin-10 gene intervention. Taken together, our results suggested that interleukin-10 gene treatment could attenuate carbon tetrachloride-induced hepatic fibrosis by inducing senescence of activated hepatic stellate cells , and this induction was closely related to p53 signaling pathway.
活化的肝星状细胞被报道在肝纤维化发生中发挥重要作用。除了活化的肝星状细胞的表型逆转和凋亡外，活化的肝星状细胞的衰老也限制了肝纤维化的发生。我们之前的研究表明，白细胞介素-10 可以通过 p53 信号通路促进肝星状细胞衰老。然而，白细胞介素-10 诱导肝纤维化中活化的肝星状细胞衰老时 p53 的表达与衰老之间的关系尚不清楚。本研究旨在探讨 p53 是否在白细胞介素-10 诱导的活化的肝星状细胞衰老和胶原降解中发挥关键作用。通过腹腔注射四氯化碳诱导肝纤维化动物模型，并通过水力转移系统转染白细胞介素-10 基因。通过腺病毒载体短发夹 RNA 敲低 p53 和 。通过肝活检和胶原染色评估纤维化的消退。通过衰老相关β-半乳糖苷酶（SA-β-Gal）染色观察肝脏中的细胞衰老。免疫组化、免疫荧光双重染色和 Western blot 分析用于评估衰老细胞和衰老相关蛋白的表达。我们的数据表明，白细胞介素-10 基因治疗可减轻四氯化碳诱导的肝纤维化，并诱导活化的肝星状细胞衰老，同时上调衰老相关蛋白的表达。我们进一步证明，敲低 p53 可消除白细胞介素-10 对衰老相关蛋白 和 的上调作用。此外，在纤维化小鼠中敲除 p53 不仅可以阻断白细胞介素-10 基因干预诱导的活化的肝星状细胞衰老，还可以阻断纤维化的降解。综上所述，我们的研究结果表明，白细胞介素-10 基因治疗通过诱导活化的肝星状细胞衰老减轻四氯化碳诱导的肝纤维化，这种诱导与 p53 信号通路密切相关。
