TGF-β1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis

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Abstract
Transforming growth factor-β1 (TGF-β1) is a powerful stimulus for collagen formation in vitro. To determine the in vivo effects of TGF-β1 on liver fibrogenesis, we generated transgenic mice overexpressing a fusion gene [C-reactive protein (CRP)/TGF-β1] consisting of the cDNA coding for an activated form of TGF-β1 under the control of the regulatory elements of the inducible human CRP gene promoter. Two transgenic lines were generated with liver-specific overexpression of mature TGF-β1. After induction of the acute phase response (15 h) with lipopolysaccharide (100 μg ip), plasma TGF-β1 levels reached >600 ng/ml in transgenic animals, which is >100 times above normal plasma levels. Basal plasma levels of uninduced transgenic animals were about two to five times above normal. As a consequence of hepatic TGF-β1 expression, we could demonstrate marked transient upregulation of procollagen I and procollagen III mRNA in the liver 15 h after the peak of TGF-β1 expression. Liver histology after repeated induction of transgene expression showed an activation of hepatic stellate cells in both transgenic lines. The fibrotic process was characterized by perisinusoidal deposition of collagen in a linear pattern. This transgenic mouse model gives in vivo evidence for the important role of TGF-β1 in stellate cell activation and liver fibrogenesis. Due to the ability to control the level of TGF-β1 expression, this model allows the study of the regulation and kinetics of collagen synthesis and fibrolysis as well as the degree of reversibility of liver fibrosis. The CRP/TGF-β1 transgenic mouse model may finally serve as a model for the testing of antifibrogenic agents.

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