Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.

TLDR

Aberrant expression of transforming growth factor beta 1 (TGF‑β1) is implicated in fibrotic and inflammatory lesions. The study aimed to assess the in vivo effects of hepatic TGF‑β1 overexpression on liver and extra‑hepatic tissues and to establish a model for testing therapies that neutralize its harmful actions. Transgenic mice were created by inserting a porcine TGF‑β1 cDNA driven by the mouse albumin promoter, yielding five lines with hepatocyte‑specific expression of the Alb/TGF‑β1 transgene. The highest‑expressing line 25 exhibited markedly elevated plasma TGF‑β1, severe hepatic fibrosis with apoptotic hepatocyte death, and multiple extra‑hepatic lesions, confirming TGF‑β1’s role in fibrotic and inflammatory disorders.

Abstract

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.