Sanderson, N. et al. Hepatic expression of mature transforming growth factor 1 in transgenic mice results in multiple tissue lesions. Proc. Natl. Acad. Sci. USA 92, 2572-2576

Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/1995; 92(7):2572-6. DOI: 10.1073/pnas.92.7.2572
Source: PubMed


Aberrant expression of transforming growth factor beta 1 (TGF-beta 1) has been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions. To determine the in vivo effects of overexpression of TGF-beta 1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-beta 1) consisting of modified porcine TGF-beta 1 cDNA under the control of the regulatory elements of the mouse albumin gene. Five transgenic lines were developed, all of which expressed the Alb/TGF-beta 1 transgene selectively in hepatocytes. The transgenic line 25 expressing the highest level of the transgene in the liver also had high (> 10-fold over control) plasma levels of TGF-beta 1. Hepatic fibrosis and apoptotic death of hepatocytes developed in all the transgenic lines but was more pronounced in line 25. The fibrotic process was characterized by deposition of collagen around individual hepatocytes and within the space of Disse in a radiating linear pattern. Several extrahepatic lesions developed in line 25, including glomerulonephritis and renal failure, arteritis and myocarditis, as well as atrophic changes in pancreas and testis. The results from this transgenic model strongly support the proposed etiological role for TGF-beta 1 in a variety of fibrotic and inflammatory disorders. The transgenic model may also provide an appropriate paradigm for testing therapeutic interventions aimed at neutralizing the detrimental effects of this important cytokine.

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Available from: Lalage M Wakefield
    • "Direct evidence for a role of TGF-β1 in renal fibrosis comes from studies reporting that, injection of human recombinant TGF-β1 in rats and rabbits leads to glomerular fibrosis (Terrell et al., 1993) and that overexpression of TGF-β in the kidney by administration of exogenous cDNA in rat renal artery lead to glomerulosclerosis characterized by ECM expansion (Isaka et al., 1993). Furthermore, transgenic mice overexpressing an active form of TGF-β1 in the liver develop progressive liver and renal fibrosis (Sanderson et al., 1995; Kopp et al., 1996). "
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    • "Using PLA of the Smad complexes in the salivary glands from these mice, we found no change in the number of BMP Smad complexes as compared with the control (Fig. 4A, 4D) but a slight increase in canonical TGF-β Smad complexes (Fig. 4B, 4E) and a substantial increase in the mixed Smad complexes (Fig. 4C, 4F). In the second model, active TGF-β1 is under the control of regulatory elements of the mouse albumin gene, which is expressed in the liver (Sanderson et al. 1995). In these mice, the resultant increase in plasma TGF-β levels leads to severe glomerulosclerosis and an accumulation of extracellular matrix in the kidney (Mozes et al. 1999). "
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    • "The three isoforms for TGF-β are β1,  β2, and β3. TGF-β1 is an important profibrogenic cytokine in liver injury and it is biologically active with multiple pharmacological actions [41]. A balance among these actions is required to maintain tissue homeostasis. "
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