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.
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.
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.