Abstract
Transforming growth factor-beta1 (TGF-β1) is a major factor in pathogenesis of chronic hepatic injury. Carbon tetrachloride (CCl4) is a liver toxicant, and CCl4-induced liver injury in mouse is a classical animal model of chemical liver injury. However, it is still unclear whether TGF-β1 is involved in the process of CCl4-induced acute chemical liver injury. The present study aimed to evaluate the role of TGF-β1 and its signaling molecule Smad3 in the acute liver injury induce by CCl4. The results showed that CCl4 induced acute liver injury in mice effectively confirmed by H&E staining of liver tissues, and levels of not only liver injury markers serum ALT and AST, but also serum TGF-β1 were elevated significantly in CCl4-treated mice, compared with the control mice treated with olive oil. Our data further revealed that TGF-β1 levels in hepatic tissue homogenate increased significantly, and type II receptor of TGF-β (TβRII) and signaling molecules Smad2, 3, mRNA expressions and Smad3 and phospho-Smad3 protein levels also increased obviously in livers of CCl4-treated mice. To clarify the effect of the elevated TGF-β1/Smad3 signaling on CCl4-induced acute liver injury, Smad3 in mouse liver was overexpressed in vivo by tail vein injection of Smad3-expressing plasmids. Upon CCl4 treatment, Smad3-overexpressing mice showed more severe liver injury identified by H&E staining of liver tissues and higher serum ALT and AST levels. Simultaneously, we found that Smad3-overexpressing mice treated with CCl4 showed more macrophages and neutrophils infiltration in liver and inflammatory cytokines IL-1β and IL-6 levels increment in serum when compared with those in control mice treated with CCl4. Moreover, the results showed that the apoptosis of hepatocytes increased significantly, and apoptosis-associated proteins Bax, cytochrome C and the cleaved caspase 3 expressions were up-regulated in CCl4-treated Smad3-overexpressing mice as well. These results suggested that TGF-β1/Smad3 signaling was activated during CCl4-induced acute liver injury in mice, and Smad3 overexpression aggravated acute liver injury by promoting inflammatory cells infiltration, inflammatory cytokines release and hepatocytes apoptosis. In conclusion, the activation of TGF-β signaling contributes to the CCl4-induced acute liver injury. Thus, TGF-β1/Smad3 may serve as a potential target for acute liver injury therapy.
Highlights
Transforming growth factor-beta (TGF-β) superfamily, which includes TGF-β, inhibins, activin and bone morphogenetic protein (BMP), possesses a wide range of biological function
The results revealed that levels of ALT and AST in sera of mice were significantly elevated on days 1 and 3 after the administration of CCl4, compared with those in control mice treated with olive oil (Fig 2A), and the increased peak was on day 1, and gradually declined
The results revealed that TGF-β1 levels increased significantly in sera of CCl4-treated mice, compared with those in control mice treated with olive oil (Fig 2B), and the levels peaked on day 1 and 3
Summary
Transforming growth factor-beta (TGF-β) superfamily, which includes TGF-β, inhibins, activin and bone morphogenetic protein (BMP), possesses a wide range of biological function. They play critical roles in early embryogenesis, neuronal differentiation induction, hematopoiesis and osteoblast proliferation and differentiation [1,2,3,4]. Signaling is initiated with TGF-β/TGF-β type II receptor (TβRII) binding and subsequently, type I receptor (TβRI) is activated. Smad is an important TGF-β signaling molecule [14] and exerts important roles in activation of hepatic stellate cells, inducing them to produce concomitant extracellular matrix [15, 16]
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