Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Oct;92(4):1812–1818. doi: 10.1172/JCI116771

Regulation of alveolar macrophage transforming growth factor-beta secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat.

N Khalil 1, C Whitman 1, L Zuo 1, D Danielpour 1, A Greenberg 1
PMCID: PMC288344  PMID: 7691887

Abstract

In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we previously demonstrated that TGF-beta was markedly elevated within 7 d of bleomycin administration. At the time of maximal TGF-beta production, TGF-beta 1 was localized by immunohistochemistry to be present almost exclusively in alveolar macrophages. In this study, we have demonstrated that alveolar macrophages stimulated by bleomycin-induced injury secrete large quantities of biologically active TGF-beta 1 when explanted into tissue culture. However, alveolar macrophages from normal saline-treated rats secrete small quantities of biologically inactive TGF-beta. In contrast, splenic macrophages secrete large quantities of inactive TGF-beta and are unaffected by the intratracheal bleomycin treatment. High doses of the corticosteroid methylprednisolone given intramuscularly before and concomitantly with bleomycin administration prevented the influx of alveolar macrophages into the lungs, diminishing both the number of macrophages present in the alveoli and the total lung content of TGF-beta. However, the rate of secretion of TGF-beta by alveolar macrophages recovered from the alveoli was unchanged after corticosteroid treatment. When activated alveolar macrophages were cultured in the presence of several concentrations of dexamethasone that completely suppressed IL-1 secretion, little effect on TGF-beta secretion was observed. The findings in this study demonstrate that during bleomycin-induced injury, alveolar macrophages not only secrete large quantities of active TGF-beta 1, but are a predominant source of the enhanced TGF-beta response seen in this model. Furthermore, the alveolar macrophage secretion of TGF-beta is not inhibited by the presence of high concentrations of corticosteroids.

Full text

PDF
1812

Selected References

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

  1. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. AyanlarBatuman O., Ferrero A. P., Diaz A., Jimenez S. A. Regulation of transforming growth factor-beta 1 gene expression by glucocorticoids in normal human T lymphocytes. J Clin Invest. 1991 Nov;88(5):1574–1580. doi: 10.1172/JCI115469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bachwich P. R., Lynch J. P., 3rd, Larrick J., Spengler M., Kunkel S. L. Tumor necrosis factor production by human sarcoid alveolar macrophages. Am J Pathol. 1986 Dec;125(3):421–425. [PMC free article] [PubMed] [Google Scholar]
  4. Border W. A., Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest. 1992 Jul;90(1):1–7. doi: 10.1172/JCI115821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Burkhardt A., Cottier H. Cellular events in alveolitis and the evolution of pulmonary fibrosis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1989;58(1):1–13. doi: 10.1007/BF02890055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chandler D. B., Hyde D. M., Giri S. N. Morphometric estimates of infiltrative cellular changes during the development of bleomycin-induced pulmonary fibrosis in hamsters. Am J Pathol. 1983 Aug;112(2):170–177. [PMC free article] [PubMed] [Google Scholar]
  7. Danielpour D., Dart L. L., Flanders K. C., Roberts A. B., Sporn M. B. Immunodetection and quantitation of the two forms of transforming growth factor-beta (TGF-beta 1 and TGF-beta 2) secreted by cells in culture. J Cell Physiol. 1989 Jan;138(1):79–86. doi: 10.1002/jcp.1041380112. [DOI] [PubMed] [Google Scholar]
  8. Danielpour D., Kim K. Y., Dart L. L., Watanabe S., Roberts A. B., Sporn M. B. Sandwich enzyme-linked immunosorbent assays (SELISAs) quantitate and distinguish two forms of transforming growth factor-beta (TGF-beta 1 and TGF-beta 2) in complex biological fluids. Growth Factors. 1989;2(1):61–71. doi: 10.3109/08977198909069082. [DOI] [PubMed] [Google Scholar]
  9. DePaso W. J., Winterbauer R. H. Interstitial lung disease. Dis Mon. 1991 Feb;37(2):61–133. [PubMed] [Google Scholar]
  10. Denholm E. M. Continuous secretion of monocyte chemotactic factors and fibroblast growth factors by alveolar macrophages following a single exposure to bleomycin in vitro. Am J Pathol. 1992 Oct;141(4):965–971. [PMC free article] [PubMed] [Google Scholar]
  11. Fitzpatrick D. R., Denhez F., Kondaiah P., Akhurst R. J. Differential expression of TGF beta isoforms in murine palatogenesis. Development. 1990 Jul;109(3):585–595. doi: 10.1242/dev.109.3.585. [DOI] [PubMed] [Google Scholar]
  12. Gearing A. J., Bird C. R., Bristow A., Poole S., Thorpe R. A simple sensitive bioassay for interleukin-1 which is unresponsive to 10(3) U/ml of interleukin-2. J Immunol Methods. 1987 May 4;99(1):7–11. doi: 10.1016/0022-1759(87)90025-1. [DOI] [PubMed] [Google Scholar]
  13. Glick A. B., Flanders K. C., Danielpour D., Yuspa S. H., Sporn M. B. Retinoic acid induces transforming growth factor-beta 2 in cultured keratinocytes and mouse epidermis. Cell Regul. 1989 Nov;1(1):87–97. doi: 10.1091/mbc.1.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Haley P. J., Muggenburg B. A., Weissman D. N., Bice D. E. Comparative morphology and morphometry of alveolar macrophages from six species. Am J Anat. 1991 Aug;191(4):401–407. doi: 10.1002/aja.1001910407. [DOI] [PubMed] [Google Scholar]
  15. Harmsen A. G., Muggenburg B. A., Snipes M. B., Bice D. E. The role of macrophages in particle translocation from lungs to lymph nodes. Science. 1985 Dec 13;230(4731):1277–1280. doi: 10.1126/science.4071052. [DOI] [PubMed] [Google Scholar]
  16. Hayashi K., Frangieh G., Wolf G., Kenyon K. R. Expression of transforming growth factor-beta in wound healing of vitamin A-deficient rat corneas. Invest Ophthalmol Vis Sci. 1989 Feb;30(2):239–247. [PubMed] [Google Scholar]
  17. Holt P. G. Alveolar macrophages. I. A simple technique for the preparation of high numbers of viable alveolar macrophages from small laboratory animals. J Immunol Methods. 1979;27(2):189–198. doi: 10.1016/0022-1759(79)90264-3. [DOI] [PubMed] [Google Scholar]
  18. Horwitz D. A., Allison A. C., Ward P., Kight N. Identification of human mononuclear leucocyte populations by esterase staining. Clin Exp Immunol. 1977 Nov;30(2):289–298. [PMC free article] [PubMed] [Google Scholar]
  19. Hunninghake G. W. Immunoregulatory functions of human alveolar macrophages. Am Rev Respir Dis. 1987 Aug;136(2):253–254. doi: 10.1164/ajrccm/136.2.253. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Jordana M., Richards C., Irving L. B., Gauldie J. Spontaneous in vitro release of alveolar-macrophage cytokines after the intratracheal instillation of bleomycin in rats. Characterization and kinetic studies. Am Rev Respir Dis. 1988 May;137(5):1135–1140. doi: 10.1164/ajrccm/137.5.1135. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Kim S. J., Glick A., Sporn M. B., Roberts A. B. Characterization of the promoter region of the human transforming growth factor-beta 1 gene. J Biol Chem. 1989 Jan 5;264(1):402–408. [PubMed] [Google Scholar]
  25. Knudsen P. J., Dinarello C. A., Strom T. B. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol. 1987 Dec 15;139(12):4129–4134. [PubMed] [Google Scholar]
  26. Lafyatis R., Lechleider R., Kim S. J., Jakowlew S., Roberts A. B., Sporn M. B. Structural and functional characterization of the transforming growth factor beta 3 promoter. A cAMP-responsive element regulates basal and induced transcription. J Biol Chem. 1990 Nov 5;265(31):19128–19136. [PubMed] [Google Scholar]
  27. 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]
  28. Mustoe T. A., Pierce G. F., Thomason A., Gramates P., Sporn M. B., Deuel T. F. Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta. Science. 1987 Sep 11;237(4820):1333–1336. doi: 10.1126/science.2442813. [DOI] [PubMed] [Google Scholar]
  29. Nathan C. F. Secretory products of macrophages. J Clin Invest. 1987 Feb;79(2):319–326. doi: 10.1172/JCI112815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Noma T., Glick A. B., Geiser A. G., O'Reilly M. A., Miller J., Roberts A. B., Sporn M. B. Molecular cloning and structure of the human transforming growth factor-beta 2 gene promoter. Growth Factors. 1991;4(4):247–255. doi: 10.3109/08977199109043910. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Postlethwaite A. E., Keski-Oja J., Moses H. L., Kang A. H. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987 Jan 1;165(1):251–256. doi: 10.1084/jem.165.1.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. Segarini P. R. TGF-beta receptors. Ciba Found Symp. 1991;157:29–50. [PubMed] [Google Scholar]
  35. Snyder D. S., Unanue E. R. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J Immunol. 1982 Nov;129(5):1803–1805. [PubMed] [Google Scholar]
  36. Szefler S. J., Norton C. E., Ball B., Gross J. M., Aida Y., Pabst M. J. IFN-gamma and LPS overcome glucocorticoid inhibition of priming for superoxide release in human monocytes. Evidence that secretion of IL-1 and tumor necrosis factor-alpha is not essential for monocyte priming. J Immunol. 1989 Jun 1;142(11):3985–3992. [PubMed] [Google Scholar]
  37. Territo M. C., Golde D. W. The function of human alveolar macrophages. J Reticuloendothel Soc. 1979 Jan;25(1):111–120. [PubMed] [Google Scholar]
  38. Wakefield L. M., Smith D. M., Masui T., Harris C. C., Sporn M. B. Distribution and modulation of the cellular receptor for transforming growth factor-beta. J Cell Biol. 1987 Aug;105(2):965–975. doi: 10.1083/jcb.105.2.965. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES