Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Mar 28;92(7):2572–2576. doi: 10.1073/pnas.92.7.2572

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

N Sanderson 1, V Factor 1, P Nagy 1, J Kopp 1, P Kondaiah 1, L Wakefield 1, A B Roberts 1, M B Sporn 1, S S Thorgeirsson 1
PMCID: PMC42260  PMID: 7708687

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.

Full text

PDF
2572

Images in this article

2573Fig. 1
on p.2573
2573Fig. 2
on p.2573
2574Fig. 3
on p.2574
2574Fig. 4
on p.2574
2574Fig. 5
on p.2574
2575Fig. 6
on p.2575

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anscher M. S., Crocker I. R., Jirtle R. L. Transforming growth factor-beta 1 expression in irradiated liver. Radiat Res. 1990 Apr;122(1):77–85. [PubMed] [Google Scholar]
  2. Assoian R. K., Komoriya A., Meyers C. A., Miller D. M., Sporn M. B. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. 1983 Jun 10;258(11):7155–7160. [PubMed] [Google Scholar]
  3. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Border W. A., Noble N. A. Transforming growth factor beta in tissue fibrosis. N Engl J Med. 1994 Nov 10;331(19):1286–1292. doi: 10.1056/NEJM199411103311907. [DOI] [PubMed] [Google Scholar]
  5. Brunner A. M., Marquardt H., Malacko A. R., Lioubin M. N., Purchio A. F. Site-directed mutagenesis of cysteine residues in the pro region of the transforming growth factor beta 1 precursor. Expression and characterization of mutant proteins. J Biol Chem. 1989 Aug 15;264(23):13660–13664. [PubMed] [Google Scholar]
  6. Castilla A., Prieto J., Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med. 1991 Apr 4;324(14):933–940. doi: 10.1056/NEJM199104043241401. [DOI] [PubMed] [Google Scholar]
  7. Czaja M. J., Weiner F. R., Flanders K. C., Giambrone M. A., Wind R., Biempica L., Zern M. A. In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J Cell Biol. 1989 Jun;108(6):2477–2482. doi: 10.1083/jcb.108.6.2477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Desmet V. J. Alcoholic liver disease. Histological features and evolution. Acta Med Scand Suppl. 1985;703:111–126. doi: 10.1111/j.0954-6820.1985.tb08909.x. [DOI] [PubMed] [Google Scholar]
  9. Evarts R. P., Nakatsukasa H., Marsden E. R., Hu Z., Thorgeirsson S. S. Expression of transforming growth factor-alpha in regenerating liver and during hepatic differentiation. Mol Carcinog. 1992;5(1):25–31. doi: 10.1002/mc.2940050107. [DOI] [PubMed] [Google Scholar]
  10. Flanders K. C., Thompson N. L., Cissel D. S., Van Obberghen-Schilling E., Baker C. C., Kass M. E., Ellingsworth L. R., Roberts A. B., Sporn M. B. Transforming growth factor-beta 1: histochemical localization with antibodies to different epitopes. J Cell Biol. 1989 Feb;108(2):653–660. doi: 10.1083/jcb.108.2.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lin H. Y., Wang X. F., Ng-Eaton E., Weinberg R. A., Lodish H. F. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell. 1992 Feb 21;68(4):775–785. doi: 10.1016/0092-8674(92)90152-3. [DOI] [PubMed] [Google Scholar]
  12. Low M. J., Hammer R. E., Goodman R. H., Habener J. F., Palmiter R. D., Brinster R. L. Tissue-specific posttranslational processing of pre-prosomatostatin encoded by a metallothionein-somatostatin fusion gene in transgenic mice. Cell. 1985 May;41(1):211–219. doi: 10.1016/0092-8674(85)90075-3. [DOI] [PubMed] [Google Scholar]
  13. Lyons R. M., Gentry L. E., Purchio A. F., Moses H. L. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol. 1990 Apr;110(4):1361–1367. doi: 10.1083/jcb.110.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lyons R. M., Moses H. L. Transforming growth factors and the regulation of cell proliferation. Eur J Biochem. 1990 Feb 14;187(3):467–473. doi: 10.1111/j.1432-1033.1990.tb15327.x. [DOI] [PubMed] [Google Scholar]
  15. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  16. Moses H. L., Yang E. Y., Pietenpol J. A. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell. 1990 Oct 19;63(2):245–247. doi: 10.1016/0092-8674(90)90155-8. [DOI] [PubMed] [Google Scholar]
  17. Murakami H., Sanderson N. D., Nagy P., Marino P. A., Merlino G., Thorgeirsson S. S. Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res. 1993 Apr 15;53(8):1719–1723. [PubMed] [Google Scholar]
  18. Nakatsukasa H., Nagy P., Evarts R. P., Hsia C. C., Marsden E., Thorgeirsson S. S. Cellular distribution of transforming growth factor-beta 1 and procollagen types I, III, and IV transcripts in carbon tetrachloride-induced rat liver fibrosis. J Clin Invest. 1990 Jun;85(6):1833–1843. doi: 10.1172/JCI114643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Oberhammer F. A., Pavelka M., Sharma S., Tiefenbacher R., Purchio A. F., Bursch W., Schulte-Hermann R. Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5408–5412. doi: 10.1073/pnas.89.12.5408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Okuda S., Languino L. R., Ruoslahti E., Border W. A. Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J Clin Invest. 1990 Aug;86(2):453–462. doi: 10.1172/JCI114731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pinkert C. A., Ornitz D. M., Brinster R. L., Palmiter R. D. An albumin enhancer located 10 kb upstream functions along with its promoter to direct efficient, liver-specific expression in transgenic mice. Genes Dev. 1987 May;1(3):268–276. doi: 10.1101/gad.1.3.268. [DOI] [PubMed] [Google Scholar]
  22. Roberts A. B., Sporn M. B. Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors. 1993;8(1):1–9. doi: 10.3109/08977199309029129. [DOI] [PubMed] [Google Scholar]
  23. Samuel S. K., Hurta R. A., Kondaiah P., Khalil N., Turley E. A., Wright J. A., Greenberg A. H. Autocrine induction of tumor protease production and invasion by a metallothionein-regulated TGF-beta 1 (Ser223, 225). EMBO J. 1992 Apr;11(4):1599–1605. doi: 10.1002/j.1460-2075.1992.tb05205.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schweizer J., Goerttler K. Synthesis in vitro of keratin polypeptides directed by mRNA isolated from newborn and adult mouse epidermis. Eur J Biochem. 1980 Nov;112(2):243–249. doi: 10.1111/j.1432-1033.1980.tb07200.x. [DOI] [PubMed] [Google Scholar]
  25. Terrell T. G., Working P. K., Chow C. P., Green J. D. Pathology of recombinant human transforming growth factor-beta 1 in rats and rabbits. Int Rev Exp Pathol. 1993;34(Pt B):43–67. doi: 10.1016/b978-0-12-364935-5.50009-2. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES