TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis.
Transforming growth factor-beta1 (TGF-beta1) is a powerful stimulus for collagen formation in vitro. To determine the in vivo effects of TGF-beta1 on liver fibrogenesis, we generated transgenic mice overexpressing a fusion gene [C-reactive protein (CRP)/TGF-beta1] consisting of the cDNA coding for an activated form of TGF-beta1 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-beta1. After induction of the acute phase response (15 h) with lipopolysaccharide (100 microgram ip), plasma TGF-beta1 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-beta1 expression, we could demonstrate marked transient upregulation of procollagen I and procollagen III mRNA in the liver 15 h after the peak of TGF-beta1 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-beta1 in stellate cell activation and liver fibrogenesis. Due to the ability to control the level of TGF-beta1 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-beta1 transgenic mouse model may finally serve as a model for the testing of antifibrogenic agents.
Kanzler
S
S
Boehringer Ingelheim Research Group, University of Mainz, 55101 Mainz, Cologne, Germany.
Lohse
A W
AW
Keil
A
A
Henninger
J
J
Dienes
H P
HP
Schirmacher
P
P
Rose-John
S
S
zum Büschenfelde
K H
KH
Blessing
M
M
D000818:Animals; D002097:C-Reactive Protein / Q000096:biosynthesis / Q000235:genetics; D003094:Collagen / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D011347:Procollagen / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D008070:Lipopolysaccharides; D011347:Procollagen; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D002097:C-Reactive Protein