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. 1991 Dec;139(6):1221–1229.

Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease.

S Milani 1, H Herbst 1, D Schuppan 1, H Stein 1, C Surrenti 1
PMCID: PMC1886459  PMID: 1750499

Abstract

Transforming growth factor (TGF) beta 1 has been implicated in the control of hepatocyte growth and stimulation of extracellular matrix synthesis in acute and chronic liver disease. The cellular localization of transforming growth factor (TGF) beta 1 and beta 2 RNA transcripts was determined in normal and fibrotic liver by in situ hybridization with [35S]-labeled RNA probes in combination with immunostaining for cell type characteristic markers. Fibrotic specimens were from patients with hepatitis B virus infection or alcohol abuse and rats with fibrosis secondary to bile duct ligation and scission. In normal liver, low levels of TGF beta 1 transcripts were found in some portal tract stromal cells, and TGF beta 2 RNA was not detectable. In fibrotic liver, high TGF beta 1 RNA levels were present in most mesenchymal liver cells, in most inflammatory cells, and in few bile duct epithelial cells. Hepatocytes did not express this cytokine with the exception of few limiting plate hepatocytes in cases of human cirrhosis with high activity. TGF beta 2 transcripts were detected at high levels in proliferating bile ducts of fibrotic livers, but were absent in all other cell types. TGF beta 1 expression in the liver is thus a function predominantly of mononuclear and mesenchymal cells as well as of some hepatocytes, whereas TGF beta 2 expression is a specific property of bile duct epithelial cells that may be related to the formation of specialized periductular connective tissue during bile duct proliferation.

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Selected References

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

  1. Albers K., Fuchs E. Expression of mutant keratin cDNAs in epithelial cells reveals possible mechanisms for initiation and assembly of intermediate filaments. J Cell Biol. 1989 Apr;108(4):1477–1493. doi: 10.1083/jcb.108.4.1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armendariz-Borunda J., Seyer J. M., Kang A. H., Raghow R. Regulation of TGF beta gene expression in rat liver intoxicated with carbon tetrachloride. FASEB J. 1990 Feb 1;4(2):215–221. doi: 10.1096/fasebj.4.2.2298342. [DOI] [PubMed] [Google Scholar]
  3. Braun L., Mead J. E., Panzica M., Mikumo R., Bell G. I., Fausto N. Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1539–1543. doi: 10.1073/pnas.85.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carr B. I., Hayashi I., Branum E. L., Moses H. L. Inhibition of DNA synthesis in rat hepatocytes by platelet-derived type beta transforming growth factor. Cancer Res. 1986 May;46(5):2330–2334. [PubMed] [Google Scholar]
  5. Carr B. I., Huang T. H., Itakura K., Noël M., Marceau N. TGF beta gene transcription in normal and neoplastic liver growth. J Cell Biochem. 1989 Apr;39(4):477–487. doi: 10.1002/jcb.240390413. [DOI] [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. Chakrabarty S., Fan D., Varani J. Modulation of differentiation and proliferation in human colon carcinoma cells by transforming growth factor beta 1 and beta 2. Int J Cancer. 1990 Sep 15;46(3):493–499. doi: 10.1002/ijc.2910460328. [DOI] [PubMed] [Google Scholar]
  8. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  9. Davis B. H. Transforming growth factor beta responsiveness is modulated by the extracellular collagen matrix during hepatic ito cell culture. J Cell Physiol. 1988 Sep;136(3):547–553. doi: 10.1002/jcp.1041360323. [DOI] [PubMed] [Google Scholar]
  10. Edwards D. R., Murphy G., Reynolds J. J., Whitham S. E., Docherty A. J., Angel P., Heath J. K. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J. 1987 Jul;6(7):1899–1904. doi: 10.1002/j.1460-2075.1987.tb02449.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ellingsworth L. R., Brennan J. E., Fok K., Rosen D. M., Bentz H., Piez K. A., Seyedin S. M. Antibodies to the N-terminal portion of cartilage-inducing factor A and transforming growth factor beta. Immunohistochemical localization and association with differentiating cells. J Biol Chem. 1986 Sep 15;261(26):12362–12367. [PubMed] [Google Scholar]
  12. Fausto N., Mead J. E. Regulation of liver growth: protooncogenes and transforming growth factors. Lab Invest. 1989 Jan;60(1):4–13. [PubMed] [Google Scholar]
  13. Friedman S. L., Roll F. J., Boyles J., Bissell D. M. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8681–8685. doi: 10.1073/pnas.82.24.8681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gruschwitz M., Müller P. U., Sepp N., Hofer E., Fontana A., Wick G. Transcription and expression of transforming growth factor type beta in the skin of progressive systemic sclerosis: a mediator of fibrosis? J Invest Dermatol. 1990 Feb;94(2):197–203. doi: 10.1111/1523-1747.ep12874503. [DOI] [PubMed] [Google Scholar]
  15. Höfler H., Pütz B., Ruhri C., Wirnsberger G., Klimpfinger M., Smolle J. Simultaneous localization of calcitonin mRNA and peptide in a medullary thyroid carcinoma. Virchows Arch B Cell Pathol Incl Mol Pathol. 1987;54(3):144–151. doi: 10.1007/BF02899206. [DOI] [PubMed] [Google Scholar]
  16. Ignotz R. A., Massagué J. Cell adhesion protein receptors as targets for transforming growth factor-beta action. Cell. 1987 Oct 23;51(2):189–197. doi: 10.1016/0092-8674(87)90146-2. [DOI] [PubMed] [Google Scholar]
  17. Ignotz R. A., Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed] [Google Scholar]
  18. Ishibashi T., Miller S. L., Burstein S. A. Type beta transforming growth factor is a potent inhibitor of murine megakaryocytopoiesis in vitro. Blood. 1987 Jun;69(6):1737–1741. [PubMed] [Google Scholar]
  19. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kountouras J., Billing B. H., Scheuer P. J. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol. 1984 Jun;65(3):305–311. [PMC free article] [PubMed] [Google Scholar]
  21. Machida C. M., Muldoon L. L., Rodland K. D., Magun B. E. Transcriptional modulation of transin gene expression by epidermal growth factor and transforming growth factor beta. Mol Cell Biol. 1988 Jun;8(6):2479–2483. doi: 10.1128/mcb.8.6.2479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Matsuoka M., Pham N. T., Tsukamoto H. Differential effects of interleukin-1 alpha, tumor necrosis factor alpha, and transforming growth factor beta 1 on cell proliferation and collagen formation by cultured fat-storing cells. Liver. 1989 Apr;9(2):71–78. doi: 10.1111/j.1600-0676.1989.tb00382.x. [DOI] [PubMed] [Google Scholar]
  23. Matsuoka M., Tsukamoto H. Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor beta: implication for a pathogenetic role in alcoholic liver fibrogenesis. Hepatology. 1990 Apr;11(4):599–605. doi: 10.1002/hep.1840110412. [DOI] [PubMed] [Google Scholar]
  24. McMahon J. B., Richards W. L., del Campo A. A., Song M. K., Thorgeirsson S. S. Differential effects of transforming growth factor-beta on proliferation of normal and malignant rat liver epithelial cells in culture. Cancer Res. 1986 Sep;46(9):4665–4671. [PubMed] [Google Scholar]
  25. Meyer D. H., Bachem M. G., Gressner A. M. Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cell-derived transforming growth factors type beta 1 and type alpha. Biochem Biophys Res Commun. 1990 Sep 28;171(3):1122–1129. doi: 10.1016/0006-291x(90)90801-s. [DOI] [PubMed] [Google Scholar]
  26. Milani S., Herbst H., Schuppan D., Hahn E. G., Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology. 1989 Jul;10(1):84–92. doi: 10.1002/hep.1840100117. [DOI] [PubMed] [Google Scholar]
  27. Milani S., Herbst H., Schuppan D., Kim K. Y., Riecken E. O., Stein H. Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. Gastroenterology. 1990 Jan;98(1):175–184. doi: 10.1016/0016-5085(90)91307-r. [DOI] [PubMed] [Google Scholar]
  28. Milani S., Herbst H., Schuppan D., Niedobitek G., Kim K. Y., Stein H. Vimentin expression of newly formed rat bile duct epithelial cells in secondary biliary fibrosis. Virchows Arch A Pathol Anat Histopathol. 1989;415(3):237–242. doi: 10.1007/BF00724910. [DOI] [PubMed] [Google Scholar]
  29. Milani S., Herbst H., Schuppan D., Riecken E. O., Stein H. Cellular localization of laminin gene transcripts in normal and fibrotic human liver. Am J Pathol. 1989 Jun;134(6):1175–1182. [PMC free article] [PubMed] [Google Scholar]
  30. Milani S., Herbst H., Schuppan D., Surrenti C., Riecken E. O., Stein H. Cellular localization of type I III and IV procollagen gene transcripts in normal and fibrotic human liver. Am J Pathol. 1990 Jul;137(1):59–70. [PMC free article] [PubMed] [Google Scholar]
  31. Mummery C. L., Slager H., Kruijer W., Feijen A., Freund E., Koornneef I., van den Eijnden-van Raaij A. J. Expression of transforming growth factor beta 2 during the differentiation of murine embryonal carcinoma and embryonic stem cells. Dev Biol. 1990 Jan;137(1):161–170. doi: 10.1016/0012-1606(90)90017-d. [DOI] [PubMed] [Google Scholar]
  32. Nakatsukasa H., Evarts R. P., Hsia C. C., Thorgeirsson S. S. Transforming growth factor-beta 1 and type I procollagen transcripts during regeneration and early fibrosis of rat liver. Lab Invest. 1990 Aug;63(2):171–180. [PubMed] [Google Scholar]
  33. 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]
  34. Raghow R., Postlethwaite A. E., Keski-Oja J., Moses H. L., Kang A. H. Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts. J Clin Invest. 1987 Apr;79(4):1285–1288. doi: 10.1172/JCI112950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roberts A. B., Sporn M. B., Assoian R. K., Smith J. M., Roche N. S., Wakefield L. M., Heine U. I., Liotta L. A., Falanga V., Kehrl J. H. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171. doi: 10.1073/pnas.83.12.4167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rossi P., Karsenty G., Roberts A. B., Roche N. S., Sporn M. B., de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta. Cell. 1988 Feb 12;52(3):405–414. doi: 10.1016/s0092-8674(88)80033-3. [DOI] [PubMed] [Google Scholar]
  37. Sporn M. B., Roberts A. B., Shull J. H., Smith J. M., Ward J. M., Sodek J. Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science. 1983 Mar 18;219(4590):1329–1331. doi: 10.1126/science.6572416. [DOI] [PubMed] [Google Scholar]
  38. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  39. Stein H., Gatter K., Asbahr H., Mason D. Y. Use of freeze-dried paraffin-embedded sections for immunohistologic staining with monoclonal antibodies. Lab Invest. 1985 Jun;52(6):676–683. [PubMed] [Google Scholar]
  40. Takehara K., LeRoy E. C., Grotendorst G. R. TGF-beta inhibition of endothelial cell proliferation: alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. Cell. 1987 May 8;49(3):415–422. doi: 10.1016/0092-8674(87)90294-7. [DOI] [PubMed] [Google Scholar]
  41. Thompson N. L., Flanders K. C., Smith J. M., Ellingsworth L. R., Roberts A. B., Sporn M. B. Expression of transforming growth factor-beta 1 in specific cells and tissues of adult and neonatal mice. J Cell Biol. 1989 Feb;108(2):661–669. doi: 10.1083/jcb.108.2.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weiner F. R., Giambrone M. A., Czaja M. J., Shah A., Annoni G., Takahashi S., Eghbali M., Zern M. A. Ito-cell gene expression and collagen regulation. Hepatology. 1990 Jan;11(1):111–117. doi: 10.1002/hep.1840110119. [DOI] [PubMed] [Google Scholar]
  43. de Martin R., Haendler B., Hofer-Warbinek R., Gaugitsch H., Wrann M., Schlüsener H., Seifert J. M., Bodmer S., Fontana A., Hofer E. Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family. EMBO J. 1987 Dec 1;6(12):3673–3677. doi: 10.1002/j.1460-2075.1987.tb02700.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. van Eyken P., Sciot R., van Damme B., de Wolf-Peeters C., Desmet V. J. Keratin immunohistochemistry in normal human liver. Cytokeratin pattern of hepatocytes, bile ducts and acinar gradient. Virchows Arch A Pathol Anat Histopathol. 1987;412(1):63–72. doi: 10.1007/BF00750732. [DOI] [PubMed] [Google Scholar]

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