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

Transforming growth factor-beta 1 (TGF-beta 1) is a powerful stimulus for collagen formation in vitro. To determine the in vivo effects of TGF-beta 1 on liver fibrogenesis, we generated transgenic mice overexpressing a fusion gene [C-reactive protein (CRP)/TGF-beta 1] consisting of the cDNA coding for an activated form of TGF-beta 1 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-beta 1. After induction of the acute phase response (15 h) with lipopolysaccharide (100 mu g ip), plasma TGF-beta 1 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-beta 1 expression, we could demonstrate marked transient upregulation of procollagen I and procollagen III mRNA in the liver 15 h after the peak of TGF-beta 1 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-beta 1 in stellate cell activation and liver fibrogenesis. Due to the ability to control the level of TGF-beta 1 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-beta 1 transgenic mouse model may finally serve as a model for the testing of antifibrogenic agents.