HEPATIC EXPRESSION OF MATURE TRANSFORMING GROWTH-FACTOR-BETA-1 IN TRANSGENIC MICE RESULTS IN MULTIPLE TISSUE LESIONS

Aberrant expression of transforming growth factor beta 1 (TGF-beta 1) has been implicated in a number of disease processes, particularly tho se involving fibrotic and inflammatory lesions. To determine the in vi vo effects of overexpression of TGF-beta 1 on the function and structu re of hepatic as well as extrahepatic tissues, transgenic mice were ge nerated containing a fusion gene (Alb/TGF-beta 1) consisting of modifi ed porcine TGF-beta 1 cDNA under the control of the regulatory element s of the mouse albumin gene. Five transgenic lines were developed, all of which expressed the Alb/TGF-beta 1 transgene selectively in hepato cytes. The transgenic line 25 expressing the highest level of the tran sgene in the liver also had high (>10-fold over control) plasma levels of TGF-beta 1. Hepatic fibrosis and apoptotic death of hepatocytes de veloped in all the transgenic lines but was more pronounced in line 25 . The fibrotic process was characterized by deposition of collagen aro und individual hepatocytes and within the space of Disse in a radiatin g linear pattern. Several extrahepatic lesions developed in line 25, i ncluding glomerulonephritis and renal failure, arteritis and myocardit is, as well as atrophic changes in pancreas and testis. The results fr om this transgenic model strongly support the proposed etiological rol e for TGF-beta 1 in a variety of fibrotic and inflammatory disorders, The transgenic model may also provide an appropriate paradigm for test ing therapeutic interventions aimed at neutralizing the detrimental ef fects of this important cytokine.