Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions

Nancy Sanderson, Valentina Factor, Peter Nagy, Jeffrey Kopp, Paturu Kondaiah, Lalage Wakefield, Anita B. Roberts, Michael B. Sporn, Snorri S. Thorgeirsson

Research output: Contribution to journalArticle

556 Citations (Scopus)

Abstract

Aberrant expression of transforming growth factor β1 (TGF-β1) 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-β1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-β1) consisting of modified porcine TGF-β1 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-β1 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-β1. 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-β1 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.

Original languageEnglish
Pages (from-to)2572-2576
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number7
DOIs
Publication statusPublished - Mar 28 1995

Fingerprint

Transforming Growth Factors
Transgenic Mice
Liver
Hepatocytes
Transgenes
Arteritis
Gene Fusion
Myocarditis
Glomerulonephritis
Renal Insufficiency
Testis
Pancreas
Albumins
Fibrosis
Swine
Collagen
Complementary DNA
Cytokines
Genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions. / Sanderson, Nancy; Factor, Valentina; Nagy, Peter; Kopp, Jeffrey; Kondaiah, Paturu; Wakefield, Lalage; Roberts, Anita B.; Sporn, Michael B.; Thorgeirsson, Snorri S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 7, 28.03.1995, p. 2572-2576.

Research output: Contribution to journalArticle

Sanderson, Nancy ; Factor, Valentina ; Nagy, Peter ; Kopp, Jeffrey ; Kondaiah, Paturu ; Wakefield, Lalage ; Roberts, Anita B. ; Sporn, Michael B. ; Thorgeirsson, Snorri S. / Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions. In: Proceedings of the National Academy of Sciences of the United States of America. 1995 ; Vol. 92, No. 7. pp. 2572-2576.
@article{85ddb1a87fb347ecbd607009e6fe5092,
title = "Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions",
abstract = "Aberrant expression of transforming growth factor β1 (TGF-β1) 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-β1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-β1) consisting of modified porcine TGF-β1 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-β1 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-β1. 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-β1 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.",
author = "Nancy Sanderson and Valentina Factor and Peter Nagy and Jeffrey Kopp and Paturu Kondaiah and Lalage Wakefield and Roberts, {Anita B.} and Sporn, {Michael B.} and Thorgeirsson, {Snorri S.}",
year = "1995",
month = "3",
day = "28",
doi = "10.1073/pnas.92.7.2572",
language = "English",
volume = "92",
pages = "2572--2576",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "7",

}

TY - JOUR

T1 - Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions

AU - Sanderson, Nancy

AU - Factor, Valentina

AU - Nagy, Peter

AU - Kopp, Jeffrey

AU - Kondaiah, Paturu

AU - Wakefield, Lalage

AU - Roberts, Anita B.

AU - Sporn, Michael B.

AU - Thorgeirsson, Snorri S.

PY - 1995/3/28

Y1 - 1995/3/28

N2 - Aberrant expression of transforming growth factor β1 (TGF-β1) 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-β1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-β1) consisting of modified porcine TGF-β1 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-β1 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-β1. 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-β1 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.

AB - Aberrant expression of transforming growth factor β1 (TGF-β1) 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-β1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-β1) consisting of modified porcine TGF-β1 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-β1 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-β1. 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-β1 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.

UR - http://www.scopus.com/inward/record.url?scp=0028953768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028953768&partnerID=8YFLogxK

U2 - 10.1073/pnas.92.7.2572

DO - 10.1073/pnas.92.7.2572

M3 - Article

C2 - 7708687

AN - SCOPUS:0028953768

VL - 92

SP - 2572

EP - 2576

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 7

ER -