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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1992 May;88(2):280–287. doi: 10.1111/j.1365-2249.1992.tb03074.x

In vivo levels and in vitro production of interferon-gamma in fibrosing interstitial lung diseases.

C Prior 1, P L Haslam 1
PMCID: PMC1554282  PMID: 1572093

Abstract

The in vivo role of interferons in the development of fibrosis is not fully understood but it is known that interferons can suppress fibroblast proliferation and collagen synthesis in vitro. We have recently demonstrated that in a group of patients with sarcoidosis having predominant pulmonary involvement, patients with the highest levels of circulating interferon-gamma (IFN-gamma) more frequently resolved on corticosteroids, suggesting that they had a less 'fibrotic' component to their disease. We now report that in two other diseases, where the tendency to develop pulmonary fibrosis is greater than in sarcoidosis, namely cryptogenic fibrosing alveolitis (CFA) and fibrosing alveolitis associated with the systemic connective tissue disease progressive systemic sclerosis (FA + PSS), very few patients have elevations in IFN-gamma in their serum. However, as in sarcoidosis, those with the highest levels responded to corticosteroids (P less than 0.05). Attempts to measure IFN-gamma levels in the lungs, using cell-free bronchoalveolar lavage (BAL) fluid supernatants, were negative in all the study groups, suggesting that these samples may be inadequate for such studies. To investigate whether there might be an intrinsic defect in T lymphocyte function associated with predisposition to fibrosing lung diseases, we then investigated the in vitro production of IFN-gamma by lymphocytes separated from the blood of 18 untreated patients (six with CFA, six with FA + PSS and six with sarcoidosis). IFN-gamma production was impaired in 10 (56%) (two with CFA, four with FA + PSS and four with sarcoidosis). A higher proportion of the fibrosing alveolitis patients (CFA or FA + PSS) with impaired IFN-gamma production have subsequently shown spontaneous lung functional deterioration. These findings suggest that impaired IFN-gamma release might be a potentiating factor in the pathogenesis of these fibrosing lung diseases.

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Selected References

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  1. Alcocer-Varela J., Martinez-Cordero E., Alarcon-Segovia D. Spontaneous production of, and defective response to, interleukin-1 by peripheral blood mononuclear cells from patients with scleroderma. Clin Exp Immunol. 1985 Mar;59(3):666–672. [PMC free article] [PubMed] [Google Scholar]
  2. Andrews B. S., Friou G. J., Barr R. J., Mirick G. R., Berman M., Sandborg C., Ross P. A. Loss of epidermal Langerhans' cells and endothelial cell HLA-DR antigens in the skin in progressive systemic sclerosis. J Rheumatol. 1986 Apr;13(2):341–348. [PubMed] [Google Scholar]
  3. Andrews B. S., Friou G. J., Berman M. A., Sandborg C. I., Mirick G. R., Cesario T. C. Changes in circulating monocytes in patients with progressive systemic sclerosis. J Rheumatol. 1987 Oct;14(5):930–935. [PubMed] [Google Scholar]
  4. Chang T. W., McKinney S., Liu V., Kung P. C., Vilcek J., Le J. Use of monoclonal antibodies as sensitive and specific probes for biologically active human gamma-interferon. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5219–5222. doi: 10.1073/pnas.81.16.5219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Czaja M. J., Weiner F. R., Eghbali M., Giambrone M. A., Eghbali M., Zern M. A. Differential effects of gamma-interferon on collagen and fibronectin gene expression. J Biol Chem. 1987 Sep 25;262(27):13348–13351. [PubMed] [Google Scholar]
  6. Degiannis D., Seibold J. R., Czarnecki M., Raskova J., Raska K., Jr Soluble and cellular markers of immune activation in patients with systemic sclerosis. Clin Immunol Immunopathol. 1990 Aug;56(2):259–270. doi: 10.1016/0090-1229(90)90147-i. [DOI] [PubMed] [Google Scholar]
  7. Duncan M. R., Berman B. Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation. J Exp Med. 1985 Aug 1;162(2):516–527. doi: 10.1084/jem.162.2.516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Elias J. A., Freundlich B., Kern J. A., Rosenbloom J. Cytokine networks in the regulation of inflammation and fibrosis in the lung. Chest. 1990 Jun;97(6):1439–1445. doi: 10.1378/chest.97.6.1439. [DOI] [PubMed] [Google Scholar]
  9. Elias J. A., Jimenez S. A., Freundlich B. Recombinant gamma, alpha, and beta interferon regulation of human lung fibroblast proliferation. Am Rev Respir Dis. 1987 Jan;135(1):62–65. doi: 10.1164/arrd.1987.135.1.62. [DOI] [PubMed] [Google Scholar]
  10. Elias J. A. Tumor necrosis factor interacts with interleukin-1 and interferons to inhibit fibroblast proliferation via fibroblast prostaglandin-dependent and -independent mechanisms. Am Rev Respir Dis. 1988 Sep;138(3):652–658. doi: 10.1164/ajrccm/138.3.652. [DOI] [PubMed] [Google Scholar]
  11. Famularo G., Procopio A., Giacomelli R., Danese C., Sacchetti S., Perego M. A., Santoni A., Tonietti G. Soluble interleukin-2 receptor, interleukin-2 and interleukin-4 in sera and supernatants from patients with progressive systemic sclerosis. Clin Exp Immunol. 1990 Sep;81(3):368–372. doi: 10.1111/j.1365-2249.1990.tb05340.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Franchimont P., Reuter A., Vrindts-Gevaert Y., Bastings M., Malaise M., Sondag C., Frere M. C., Gysen P. Production of tumour necrosis factor-alpha, interferon-gamma and interleukin-2 by peripheral blood mononuclear cells of subjects suffering from rheumatoid arthritis. Scand J Rheumatol. 1988;17(3):203–212. doi: 10.3109/03009748809098783. [DOI] [PubMed] [Google Scholar]
  13. Fulmer J. D. An introduction to the interstitial lung diseases. Clin Chest Med. 1982 Sep;3(3):457–473. [PubMed] [Google Scholar]
  14. Hancock W. W., Kobzik L., Colby A. J., O'Hara C. J., Cooper A. G., Godleski J. J. Detection of lymphokines and lymphokine receptors in pulmonary sarcoidosis. Immunohistologic evidence that inflammatory macrophages express IL-2 receptors. Am J Pathol. 1986 Apr;123(1):1–8. [PMC free article] [PubMed] [Google Scholar]
  15. Haslam P. L. Evaluation of alveolitis by studies of lung biopsies. Lung. 1990;168 (Suppl):984–992. doi: 10.1007/BF02718236. [DOI] [PubMed] [Google Scholar]
  16. Holt P. G. Down-regulation of immune responses in the lower respiratory tract: the role of alveolar macrophages. Clin Exp Immunol. 1986 Feb;63(2):261–270. [PMC free article] [PubMed] [Google Scholar]
  17. Hyde D. M., Henderson T. S., Giri S. N., Tyler N. K., Stovall M. Y. Effect of murine gamma interferon on the cellular responses to bleomycin in mice. Exp Lung Res. 1988;14(5):687–704. doi: 10.3109/01902148809087837. [DOI] [PubMed] [Google Scholar]
  18. Jasny B. R., Pfeffer L. M., Tamm I. Effects of beta interferon on human fibroblasts at different population doubling levels. Proliferation, cell volume, thymidine uptake, and DNA synthesis. J Exp Med. 1984 Jun 1;159(6):1741–1749. doi: 10.1084/jem.159.6.1741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kahan A., Amor B., Menkes C. J., Strauch G. Recombinant interferon-gamma in the treatment of systemic sclerosis. Am J Med. 1989 Sep;87(3):273–277. doi: 10.1016/s0002-9343(89)80150-0. [DOI] [PubMed] [Google Scholar]
  20. Kradin R. L., Divertie M. B., Colvin R. B., Ramirez J., Ryu J., Carpenter H. A., Bhan A. K. Usual interstitial pneumonitis is a T-cell alveolitis. Clin Immunol Immunopathol. 1986 Aug;40(2):224–235. doi: 10.1016/0090-1229(86)90025-5. [DOI] [PubMed] [Google Scholar]
  21. Mitchell D. N., Rees R. J. A transmissible agent from sarcoid tissue. Lancet. 1969 Jul 12;2(7611):81–84. doi: 10.1016/s0140-6736(69)92392-7. [DOI] [PubMed] [Google Scholar]
  22. Moseley P. L., Hemken C., Monick M., Nugent K., Hunninghake G. W. Interferon and growth factor activity for human lung fibroblasts. Release from bronchoalveolar cells from patients with active sarcoidosis. Chest. 1986 May;89(5):657–662. doi: 10.1378/chest.89.5.657. [DOI] [PubMed] [Google Scholar]
  23. Nagai S., Fujimura N., Hirata T., Izumi T. Differentiation between idiopathic pulmonary fibrosis and interstitial pneumonia associated with collagen vascular diseases by comparison of the ratio of OKT4+ cells and OKT8+ cells in BALF T lymphocytes. Eur J Respir Dis. 1985 Jul;67(1):1–9. [PubMed] [Google Scholar]
  24. O'Kelly P., Thomsen L., Tilles J. G., Cesario T. Inactivation of interferon by serum and synovial fluids. Proc Soc Exp Biol Med. 1985 Mar;178(3):407–411. doi: 10.3181/00379727-178-42024. [DOI] [PubMed] [Google Scholar]
  25. Pfeffer L. M., Murphy J. S., Tamm I. Interferon effects on the growth and division of human fibroblasts. Exp Cell Res. 1979 Jun;121(1):111–120. doi: 10.1016/0014-4827(79)90450-6. [DOI] [PubMed] [Google Scholar]
  26. Prior C., Haslam P. L. Increased levels of serum interferon-gamma in pulmonary sarcoidosis and relationship with response to corticosteroid therapy. Am Rev Respir Dis. 1991 Jan;143(1):53–60. doi: 10.1164/ajrccm/143.1.53. [DOI] [PubMed] [Google Scholar]
  27. Robinson B. W., McLemore T. L., Crystal R. G. Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin Invest. 1985 May;75(5):1488–1495. doi: 10.1172/JCI111852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Robinson B. W., Rose A. H. Pulmonary gamma interferon production in patients with fibrosing alveolitis. Thorax. 1990 Feb;45(2):105–108. doi: 10.1136/thx.45.2.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rosenbloom J., Feldman G., Freundlich B., Jimenez S. A. Transcriptional control of human diploid fibroblast collagen synthesis by gamma-interferon. Biochem Biophys Res Commun. 1984 Aug 30;123(1):365–372. doi: 10.1016/0006-291x(84)90422-4. [DOI] [PubMed] [Google Scholar]
  30. Rudd R. M., Haslam P. L., Turner-Warwick M. Cryptogenic fibrosing alveolitis. Relationships of pulmonary physiology and bronchoalveolar lavage to response to treatment and prognosis. Am Rev Respir Dis. 1981 Jul;124(1):1–8. doi: 10.1164/arrd.1981.124.1.1. [DOI] [PubMed] [Google Scholar]
  31. Sandborg C. I., Berman M. A., Andrews B. S., Friou G. J. Interleukin-1 production by mononuclear cells from patients with scleroderma. Clin Exp Immunol. 1985 May;60(2):294–302. [PMC free article] [PubMed] [Google Scholar]
  32. Sandborg C. I., Berman M. A., Andrews B. S., Mirick G. R., Friou G. J. Increased production of an interleukin 1 (IL-1) inhibitor with fibroblast stimulating activity by mononuclear cells from patients with scleroderma. Clin Exp Immunol. 1986 Nov;66(2):312–319. [PMC free article] [PubMed] [Google Scholar]
  33. Stephenson M. L., Krane S. M., Amento E. P., McCroskery P. A., Byrne M. Immune interferon inhibits collagen synthesis by rheumatoid synovial cells associated with decreased levels of the procollagen mRNAs. FEBS Lett. 1985 Jan 21;180(1):43–50. doi: 10.1016/0014-5793(85)80227-1. [DOI] [PubMed] [Google Scholar]
  34. Stolzenburg T., Binz H., Fontana A., Felder M., Wagenhaeuser F. J. Impaired mitogen-induced interferon-gamma production in rheumatoid arthritis and related diseases. Scand J Immunol. 1988 Jan;27(1):73–81. doi: 10.1111/j.1365-3083.1988.tb02324.x. [DOI] [PubMed] [Google Scholar]
  35. Strickland B. Imaging fibrosing alveolitis. Postgrad Med J. 1988;64 (Suppl 4):35–40. [PubMed] [Google Scholar]
  36. Taniguchi T. Regulation of cytokine gene expression. Annu Rev Immunol. 1988;6:439–464. doi: 10.1146/annurev.iy.06.040188.002255. [DOI] [PubMed] [Google Scholar]
  37. Turner-Warwick M., Burrows B., Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax. 1980 Mar;35(3):171–180. doi: 10.1136/thx.35.3.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Turner-Warwick M., Haslam P. L. The value of serial bronchoalveolar lavages in assessing the clinical progress of patients with cryptogenic fibrosing alveolitis. Am Rev Respir Dis. 1987 Jan;135(1):26–34. doi: 10.1164/arrd.1987.135.1.26. [DOI] [PubMed] [Google Scholar]
  39. Venet A., Hance A. J., Saltini C., Robinson B. W., Crystal R. G. Enhanced alveolar macrophage-mediated antigen-induced T-lymphocyte proliferation in sarcoidosis. J Clin Invest. 1985 Jan;75(1):293–301. doi: 10.1172/JCI111688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Vergnon J. M., Vincent M., de Thé G., Mornex J. F., Weynants P., Brune J. Cryptogenic fibrosing alveolitis and Epstein-Barr virus: an association? Lancet. 1984 Oct 6;2(8406):768–771. doi: 10.1016/s0140-6736(84)90702-5. [DOI] [PubMed] [Google Scholar]
  41. Vilcek J., Palombella V. J., Henriksen-DeStefano D., Swenson C., Feinman R., Hirai M., Tsujimoto M. Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors. J Exp Med. 1986 Mar 1;163(3):632–643. doi: 10.1084/jem.163.3.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wilsher M. L., Hughes D. A., Haslam P. L. Immunoregulatory properties of pulmonary surfactant: effect of lung lining fluid on proliferation of human blood lymphocytes. Thorax. 1988 May;43(5):354–359. doi: 10.1136/thx.43.5.354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wilsher M. L., Parker D. J., Haslam P. L. Immunosuppression by pulmonary surfactant: mechanisms of action. Thorax. 1990 Jan;45(1):3–8. doi: 10.1136/thx.45.1.3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Woloszczuk W. A sensitive immunoradiometric assay for gamma interferon, suitable for its measurement in serum. Clin Chem. 1985 Jun;31(6):1090–1090. [PubMed] [Google Scholar]

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