Skip to main content
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1997 Sep;105(Suppl 5):1197–1203. doi: 10.1289/ehp.97105s51197

Immunohistochemical localization of transforming growth factor beta isoforms in asbestos-related diseases.

J Jagirdar 1, T C Lee 1, J Reibman 1, L I Gold 1, C Aston 1, R Bégin 1, W N Rom 1
PMCID: PMC1470128  PMID: 9400723

Abstract

Transforming growth factor beta (TGF-beta), a multifunctional cytokine and growth factor, plays a key role in scarring and fibrotic processes because of its ability to induce extracellular matrix proteins and modulate the growth and immune function of many cell types. These effects are important in inflammatory disorders with fibrosis and cancer. The asbestos-related diseases are characterized by fibrosis in the lower respiratory tract and pleura and increased occurrence of lung cancer and mesothelioma. We performed immunohistochemistry with isoform-specific antibodies to the three TGF-beta isoforms on 16 autopsy lungs from Quebec, Canada, asbestos miners and millers. There was increased immunolocalization of all three TGF-beta isoforms in the fibrotic lesions of asbestosis and pleural fibrosis. The hyperplastic type II pneumocytes contained all three isoforms. By contrast, there was differential spatial immunostaining for the TGF-beta isoforms in malignant mesothelioma, with TGF-beta 1 in the stroma but TGF-beta 2 in the tumor cells. These data are consistent with an important role for TGF-beta in accumulation of extracellular matrix and cell proliferation in asbestos-related diseases.

Full text

PDF
1197

Images in this article

Selected References

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

  1. Alexandrow M. G., Moses H. L. Transforming growth factor beta and cell cycle regulation. Cancer Res. 1995 Apr 1;55(7):1452–1457. [PubMed] [Google Scholar]
  2. 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]
  3. Broekelmann T. J., Limper A. H., Colby T. V., McDonald J. A. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6642–6646. doi: 10.1073/pnas.88.15.6642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Corrin B., Butcher D., McAnulty B. J., Dubois R. M., Black C. M., Laurent G. J., Harrison N. K. Immunohistochemical localization of transforming growth factor-beta 1 in the lungs of patients with systemic sclerosis, cryptogenic fibrosing alveolitis and other lung disorders. Histopathology. 1994 Feb;24(2):145–150. doi: 10.1111/j.1365-2559.1994.tb01293.x. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Frank S., Madlener M., Werner S. Transforming growth factors beta1, beta2, and beta3 and their receptors are differentially regulated during normal and impaired wound healing. J Biol Chem. 1996 Apr 26;271(17):10188–10193. doi: 10.1074/jbc.271.17.10188. [DOI] [PubMed] [Google Scholar]
  7. Gerwin B. I. Cytokine signaling in mesothelial cells: receptor expression closes the autocrine loop. Am J Respir Cell Mol Biol. 1996 Jun;14(6):505–507. doi: 10.1165/ajrcmb.14.6.8652178. [DOI] [PubMed] [Google Scholar]
  8. Giri S. N., Hyde D. M., Hollinger M. A. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax. 1993 Oct;48(10):959–966. doi: 10.1136/thx.48.10.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hannon G. J., Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994 Sep 15;371(6494):257–261. doi: 10.1038/371257a0. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Jagirdar J., Begin R., Dufresne A., Goswami S., Lee T. C., Rom W. N. Transforming growth factor-beta (TGF-beta) in silicosis. Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 1):1076–1081. doi: 10.1164/ajrccm.154.4.8887610. [DOI] [PubMed] [Google Scholar]
  12. Janssen Y. M., Heintz N. H., Marsh J. P., Borm P. J., Mossman B. T. Induction of c-fos and c-jun proto-oncogenes in target cells of the lung and pleura by carcinogenic fibers. Am J Respir Cell Mol Biol. 1994 Nov;11(5):522–530. doi: 10.1165/ajrcmb.11.5.7946382. [DOI] [PubMed] [Google Scholar]
  13. Kapanci Y., Desmouliere A., Pache J. C., Redard M., Gabbiani G. Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis. Possible role of transforming growth factor beta and tumor necrosis factor alpha. Am J Respir Crit Care Med. 1995 Dec;152(6 Pt 1):2163–2169. doi: 10.1164/ajrccm.152.6.8520791. [DOI] [PubMed] [Google Scholar]
  14. Keski-Oja J., Raghow R., Sawdey M., Loskutoff D. J., Postlethwaite A. E., Kang A. H., Moses H. L. Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells. J Biol Chem. 1988 Mar 5;263(7):3111–3115. [PubMed] [Google Scholar]
  15. Khalil N., Bereznay O., Sporn M., Greenberg A. H. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation. J Exp Med. 1989 Sep 1;170(3):727–737. doi: 10.1084/jem.170.3.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Khalil N., O'Connor R. N., Flanders K. C., Unruh H. TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study. Am J Respir Cell Mol Biol. 1996 Feb;14(2):131–138. doi: 10.1165/ajrcmb.14.2.8630262. [DOI] [PubMed] [Google Scholar]
  17. Khalil N., O'Connor R. N., Unruh H. W., Warren P. W., Flanders K. C., Kemp A., Bereznay O. H., Greenberg A. H. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 1991 Aug;5(2):155–162. doi: 10.1165/ajrcmb/5.2.155. [DOI] [PubMed] [Google Scholar]
  18. Khalil N., Whitman C., Zuo L., Danielpour D., Greenberg A. Regulation of alveolar macrophage transforming growth factor-beta secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat. J Clin Invest. 1993 Oct;92(4):1812–1818. doi: 10.1172/JCI116771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kim S. J., Romeo D., Yoo Y. D., Park K. Transforming growth factor-beta: expression in normal and pathological conditions. Horm Res. 1994;42(1-2):5–8. doi: 10.1159/000184136. [DOI] [PubMed] [Google Scholar]
  20. Kim S. J., Wagner S., Liu F., O'Reilly M. A., Robbins P. D., Green M. R. Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2. Nature. 1992 Jul 23;358(6384):331–334. doi: 10.1038/358331a0. [DOI] [PubMed] [Google Scholar]
  21. Lee T. C., Gold L. I., Reibman J., Aston C., Bégin R., Rom W. N., Jagirdar J. Immunohistochemical localization of transforming growth factor-beta and insulin-like growth factor-I in asbestosis in the sheep model. Int Arch Occup Environ Health. 1997;69(3):157–164. doi: 10.1007/s004200050132. [DOI] [PubMed] [Google Scholar]
  22. Lee T. C., Zhang Y., Aston C., Hintz R., Jagirdar J., Perle M. A., Burt M., Rom W. N. Normal human mesothelial cells and mesothelioma cell lines express insulin-like growth factor I and associated molecules. Cancer Res. 1993 Jun 15;53(12):2858–2864. [PubMed] [Google Scholar]
  23. Li C. Y., Suardet L., Little J. B. Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect. J Biol Chem. 1995 Mar 10;270(10):4971–4974. doi: 10.1074/jbc.270.10.4971. [DOI] [PubMed] [Google Scholar]
  24. Maeda J., Ueki N., Ohkawa T., Iwahashi N., Nakano T., Hada T., Higashino K. Transforming growth factor-beta 1 (TGF-beta 1)- and beta 2-like activities in malignant pleural effusions caused by malignant mesothelioma or primary lung cancer. Clin Exp Immunol. 1994 Nov;98(2):319–322. doi: 10.1111/j.1365-2249.1994.tb06144.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Pelton R. W., Saxena B., Jones M., Moses H. L., Gold L. I. Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol. 1991 Nov;115(4):1091–1105. doi: 10.1083/jcb.115.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Perdue T. D., Brody A. R. Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats. J Histochem Cytochem. 1994 Aug;42(8):1061–1070. doi: 10.1177/42.8.8027525. [DOI] [PubMed] [Google Scholar]
  28. Pietenpol J. A., Stein R. W., Moran E., Yaciuk P., Schlegel R., Lyons R. M., Pittelkow M. R., Münger K., Howley P. M., Moses H. L. TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell. 1990 Jun 1;61(5):777–785. doi: 10.1016/0092-8674(90)90188-k. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Raghow R. Role of transforming growth factor-beta in repair and fibrosis. Chest. 1991 Mar;99(3 Suppl):61S–65S. doi: 10.1378/chest.99.3_supplement.61s. [DOI] [PubMed] [Google Scholar]
  31. Rom W. N., Travis W. D., Brody A. R. Cellular and molecular basis of the asbestos-related diseases. Am Rev Respir Dis. 1991 Feb;143(2):408–422. doi: 10.1164/ajrccm/143.2.408. [DOI] [PubMed] [Google Scholar]
  32. Santana A., Saxena B., Noble N. A., Gold L. I., Marshall B. C. Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 1995 Jul;13(1):34–44. doi: 10.1165/ajrcmb.13.1.7541221. [DOI] [PubMed] [Google Scholar]
  33. Sheppard D., Cohen D. S., Wang A., Busk M. Transforming growth factor beta differentially regulates expression of integrin subunits in guinea pig airway epithelial cells. J Biol Chem. 1992 Aug 25;267(24):17409–17414. [PubMed] [Google Scholar]
  34. Taipale J., Miyazono K., Heldin C. H., Keski-Oja J. Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol. 1994 Jan;124(1-2):171–181. doi: 10.1083/jcb.124.1.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zhang K., Flanders K. C., Phan S. H. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis. Am J Pathol. 1995 Aug;147(2):352–361. [PMC free article] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES