Hanchao Li1, Qian Li1, Xueting Zhang2, Xiaoyan Zheng1, Qiannan Zhang2, Zhiming Hao1. 1. Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China. 2. Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Abstract
BACKGROUND: The present study aimed to clarify the effects of thymosin β4 (Tβ4) on CCl4 -induced hepatic fibrosis in mice and to further explore the underlying mechanisms. METHODS: 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 CCl4 -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. RESULTS: The expression of Tβ4 was down-regulated in fibrotic mouse livers but was rapidly up-regulated by CCl4 -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 CCl4 -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. CONCLUSIONS: 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.
BACKGROUND: The present study aimed to clarify the effects of thymosin β4 (Tβ4) on CCl4 -induced hepatic fibrosis in mice and to further explore the underlying mechanisms. METHODS: 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 CCl4 -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. RESULTS: The expression of Tβ4 was down-regulated in fibrotic mouse livers but was rapidly up-regulated by CCl4 -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 CCl4 -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. CONCLUSIONS: 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.
Authors: Ying Zhu; Mirko Scheibinger; Daniel Christian Ellwanger; Jocelyn F Krey; Dongseok Choi; Ryan T Kelly; Stefan Heller; Peter G Barr-Gillespie Journal: Elife Date: 2019-11-04 Impact factor: 8.140