Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
J Gene Med. 2018 Sep;20(9):e3043. doi: 10.1002/jgm.3043. Epub 2018 Aug 15.
The present study aimed to clarify the effects of thymosin β4 (Tβ4) on CCl -induced hepatic fibrosis in mice and to further explore the underlying mechanisms.
Expression of Tβ4 in fibrotic liver tissues was assessed by a quantitative real time-reverse transcriptase polymerase chain reaction and immunohistochemistry. The effects of intraperitoneal adeno-associated virus-Tβ4 (AAV-Tβ4) on CCl -induced hepatic fibrosis were observed by the evaluation of collagen deposition, hepatic stellate cell (HSC) activation and pro-fibrotic cytokine expression. In vitro tests with HSCs and hepatocytes were performed to confirm the effects of Tβ4.
The expression of Tβ4 was down-regulated in fibrotic mouse livers but was rapidly up-regulated by CCl -induced acute injury. AAV-Tβ4 pre-treatment significantly attenuated liver injury, collagen deposition, HSC activation and pro-fibrotic cytokine over-expression, such as transforming growth factor β1 (TGF-β1), platelet-derived growth factor B (PDGF-B), connective tissue growth factor (CTGF) and plasminogen activator inhibitor-1 (PAI-1) in CCl -intoxicated mouse livers. In vitro experiments showed that Tβ4 suppressed HSC proliferation, blunted TGF-β1-induced HSC activation and reduced TGF-β1-induced TGF-β1, PDGF-B, CTGF and PAI-1 expression in both HSCs and hepatocytes. Ectopic Tβ4 ameliorated the over-expression of TGF-β receptor-II (TGF-βRII) in the fibrotic mouse livers. Exogenous Tβ4 down-regulated TGF-βRII expression, whereas neutralizing endogenous extracellular Tβ4 with a specific antibody up-regulated TGF-βRII expression in cultured HSCs and hepatocytes.
Tβ4 possesses anti-fibrotic activity in the liver, which is attributable, at least partly, to down-regulating TGF-βRII and thereby blunting TGF-β1-mediated fibrogenetic signaling in both HSCs and hepatocytes.
本研究旨在阐明胸腺肽β4（Tβ4）对 CCl4 诱导的肝纤维化小鼠的影响，并进一步探讨其潜在机制。
通过实时定量逆转录聚合酶链反应和免疫组织化学检测纤维化肝组织中 Tβ4 的表达。通过评估胶原沉积、肝星状细胞（HSC）激活和促纤维化细胞因子表达，观察腹腔内腺相关病毒-Tβ4（AAV-Tβ4）对 CCl4 诱导的肝纤维化的影响。通过 HSCs 和肝细胞的体外试验证实 Tβ4 的作用。
Tβ4 在纤维化小鼠肝脏中的表达下调，但 CCl4 诱导的急性损伤可迅速上调。AAV-Tβ4 预处理可显著减轻 CCl4 中毒小鼠肝脏损伤、胶原沉积、HSC 激活和促纤维化细胞因子过度表达，如转化生长因子β1（TGF-β1）、血小板衍生生长因子 B（PDGF-B）、结缔组织生长因子（CTGF）和纤溶酶原激活物抑制剂-1（PAI-1）。体外实验表明，Tβ4 抑制 HSC 增殖，减弱 TGF-β1 诱导的 HSC 激活，并降低 TGF-β1、PDGF-B、CTGF 和 PAI-1 在 HSCs 和肝细胞中的表达。外源性 Tβ4 改善了纤维化小鼠肝脏中 TGF-β 受体 II（TGF-βRII）的过度表达。外源性 Tβ4 下调 TGF-βRII 表达，而用特异性抗体中和细胞外 Tβ4 则上调培养的 HSCs 和肝细胞中的 TGF-βRII 表达。
Tβ4 在肝脏中具有抗纤维化活性，至少部分归因于下调 TGF-βRII，从而减弱 TGF-β1 在 HSCs 和肝细胞中的介导的纤维发生信号。
