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. 1995 Oct 10;92(21):9570–9574. doi: 10.1073/pnas.92.21.9570

A histologically distinctive interstitial pneumonia induced by overexpression of the interleukin 6, transforming growth factor beta 1, or platelet-derived growth factor B gene.

M Yoshida 1, J Sakuma 1, S Hayashi 1, K Abe 1, I Saito 1, S Harada 1, M Sakatani 1, S Yamamoto 1, N Matsumoto 1, Y Kaneda 1, et al.
PMCID: PMC40843  PMID: 7568174

Abstract

Interstitial pneumonia is characterized by alveolitis with resulting fibrosis of the interstitium. To determine the relevance of humoral factors in the pathogenesis of interstitial pneumonia, we introduced expression vectors into Wistar rats via the trachea to locally overexpress humoral factors in the lungs. Human interleukin (IL) 6 and IL-6 receptor genes induced lymphocytic alveolitis without marked fibroblast proliferation. In contrast, overexpression of human transforming growth factor beta 1 or human platelet-derived growth factor B gene induced only mild or apparent cellular infiltration in the alveoli, respectively. However, both factors induced significant proliferation of fibroblasts and deposition of collagen fibrils. These histopathologic changes induced by the transforming growth factor beta 1 and platelet-derived growth factor B gene are partly akin to those changes seen in lung tissues from patients with pulmonary fibrosis and markedly contrast with the changes induced by overexpression of the IL-6 and IL-6 receptor genes that mimics lymphocytic interstitial pneumonia.

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Selected References

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

  1. Battegay E. J., Raines E. W., Seifert R. A., Bowen-Pope D. F., Ross R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell. 1990 Nov 2;63(3):515–524. doi: 10.1016/0092-8674(90)90448-n. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Carré P. C., Mortenson R. L., King T. E., Jr, Noble P. W., Sable C. L., Riches D. W. Increased expression of the interleukin-8 gene by alveolar macrophages in idiopathic pulmonary fibrosis. A potential mechanism for the recruitment and activation of neutrophils in lung fibrosis. J Clin Invest. 1991 Dec;88(6):1802–1810. doi: 10.1172/JCI115501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Fine A., Goldstein R. H. The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts. J Biol Chem. 1987 Mar 15;262(8):3897–3902. [PubMed] [Google Scholar]
  5. Hirata Y., Taga T., Hibi M., Nakano N., Hirano T., Kishimoto T. Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies. J Immunol. 1989 Nov 1;143(9):2900–2906. [PubMed] [Google Scholar]
  6. Hirota H., Yoshida K., Kishimoto T., Taga T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4862–4866. doi: 10.1073/pnas.92.11.4862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Isaka Y., Fujiwara Y., Ueda N., Kaneda Y., Kamada T., Imai E. Glomerulosclerosis induced by in vivo transfection of transforming growth factor-beta or platelet-derived growth factor gene into the rat kidney. J Clin Invest. 1993 Dec;92(6):2597–2601. doi: 10.1172/JCI116874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kato K., Kaneda Y., Sakurai M., Nakanishi M., Okada Y. Direct injection of hepatitis B virus DNA into liver induced hepatitis in adult rats. J Biol Chem. 1991 Nov 25;266(33):22071–22074. [PubMed] [Google Scholar]
  9. Kelley J. Cytokines of the lung. Am Rev Respir Dis. 1990 Mar;141(3):765–788. doi: 10.1164/ajrccm/141.3.765. [DOI] [PubMed] [Google Scholar]
  10. Korfhagen T. R., Swantz R. J., Wert S. E., McCarty J. M., Kerlakian C. B., Glasser S. W., Whitsett J. A. Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice. J Clin Invest. 1994 Apr;93(4):1691–1699. doi: 10.1172/JCI117152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Martinet Y., Rom W. N., Grotendorst G. R., Martin G. R., Crystal R. G. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med. 1987 Jul 23;317(4):202–209. doi: 10.1056/NEJM198707233170404. [DOI] [PubMed] [Google Scholar]
  12. Matsuda T., Hirano T., Kishimoto T. Establishment of an interleukin 6 (IL 6)/B cell stimulatory factor 2-dependent cell line and preparation of anti-IL 6 monoclonal antibodies. Eur J Immunol. 1988 Jun;18(6):951–956. doi: 10.1002/eji.1830180618. [DOI] [PubMed] [Google Scholar]
  13. Perkins R. C., Scheule R. K., Hamilton R., Gomes G., Freidman G., Holian A. Human alveolar macrophage cytokine release in response to in vitro and in vivo asbestos exposure. Exp Lung Res. 1993 Jan-Mar;19(1):55–65. doi: 10.3109/01902149309071080. [DOI] [PubMed] [Google Scholar]
  14. Pierce G. F., Mustoe T. A., Lingelbach J., Masakowski V. R., Gramates P., Deuel T. F. Transforming growth factor beta reverses the glucocorticoid-induced wound-healing deficit in rats: possible regulation in macrophages by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2229–2233. doi: 10.1073/pnas.86.7.2229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Saito I., Oya Y., Yamamoto K., Yuasa T., Shimojo H. Construction of nondefective adenovirus type 5 bearing a 2.8-kilobase hepatitis B virus DNA near the right end of its genome. J Virol. 1985 Jun;54(3):711–719. doi: 10.1128/jvi.54.3.711-719.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Saito M., Yoshida K., Hibi M., Taga T., Kishimoto T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992 Jun 15;148(12):4066–4071. [PubMed] [Google Scholar]
  18. Sellheyer K., Bickenbach J. R., Rothnagel J. A., Bundman D., Longley M. A., Krieg T., Roche N. S., Roberts A. B., Roop D. R. Inhibition of skin development by overexpression of transforming growth factor beta 1 in the epidermis of transgenic mice. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5237–5241. doi: 10.1073/pnas.90.11.5237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Strimlan C. V., Rosenow E. C., 3rd, Weiland L. H., Brown L. R. Lymphocytic interstitial pneumonitis. Review of 13 cases. Ann Intern Med. 1978 May;88(5):616–621. doi: 10.7326/0003-4819-88-5-616. [DOI] [PubMed] [Google Scholar]
  20. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  21. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Tamura T., Udagawa N., Takahashi N., Miyaura C., Tanaka S., Yamada Y., Koishihara Y., Ohsugi Y., Kumaki K., Taga T. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11924–11928. doi: 10.1073/pnas.90.24.11924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Yang Y., Nunes F. A., Berencsi K., Furth E. E., Gönczöl E., Wilson J. M. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407–4411. doi: 10.1073/pnas.91.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Zhang Y., Lee T. C., Guillemin B., Yu M. C., Rom W. N. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol. 1993 May 1;150(9):4188–4196. [PubMed] [Google Scholar]

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