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. 1987 Apr;79(4):1254–1258. doi: 10.1172/JCI112945

Gamma-interferon inhibits collagen synthesis in vivo in the mouse.

R D Granstein, G F Murphy, R J Margolis, M H Byrne, E P Amento
PMCID: PMC424325  PMID: 3104404

Abstract

Subcutaneous implantation of osmotic pumps into CAF1 mice resulted in the formation of thick fibrous capsules around the pumps. When pumps were loaded with recombinant murine gamma-interferon (rMuIFN-gamma) to deliver 2 X 10(3) U/h for 14 d, there was a marked decrease in thickness and collagen content of the capsules from rMuIFN-gamma-treated animals compared with capsules from animals receiving diluent alone. The collagen content of the capsules was estimated by hydroxyproline analysis of the tissue and by quantitative electron microscopy of collagen bundles. Heat-inactivated rMuIFN-gamma failed to reduce the fibrotic response in this assay. These results provide compelling evidence that gamma-interferon can down-regulate collagen synthesis in vivo and suggest the possibility that this lymphokine may be useful in the treatment of disease states characterized by excessive fibrosis.

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Selected References

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

  1. Abla A. A., Maroon J. C., Kennerdell J. S., Deeb Z. L. Fibrosis surrounding a silicone implant simulating recurrent orbital meningioma. Case report. J Neurosurg. 1985 Sep;63(3):467–469. doi: 10.3171/jns.1985.63.3.0467. [DOI] [PubMed] [Google Scholar]
  2. Amento E. P., Bhan A. K., McCullagh K. G., Krane S. M. Influences of gamma interferon on synovial fibroblast-like cells. Ia induction and inhibition of collagen synthesis. J Clin Invest. 1985 Aug;76(2):837–848. doi: 10.1172/JCI112041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chvapil M., Koopmann C. F., Jr Scar formation: physiology and pathological states. Otolaryngol Clin North Am. 1984 May;17(2):265–272. [PubMed] [Google Scholar]
  4. Crystal R. G., Fulmer J. D., Roberts W. C., Moss M. L., Line B. R., Reynolds H. Y. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. 1976 Dec;85(6):769–788. doi: 10.7326/0003-4819-85-6-769. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Duncan M. R., Perlish J. S., Fleischmajer R. Lymphokine/monokine inhibition of fibroblast proliferation and collagen production: role in progressive systemic sclerosis (PSS). J Invest Dermatol. 1984 Nov;83(5):377–384. doi: 10.1111/1523-1747.ep12264686. [DOI] [PubMed] [Google Scholar]
  7. Elliott M. P., Juler G. L. Comparison of Marlex mesh and microporous teflon sheets when used for hernia repair in the experimental animal. Am J Surg. 1979 Mar;137(3):342–344. doi: 10.1016/0002-9610(79)90063-1. [DOI] [PubMed] [Google Scholar]
  8. Fleischmajer R., Perlish J. S., Duncan M. Scleroderma. A model for fibrosis. Arch Dermatol. 1983 Dec;119(12):957–962. doi: 10.1001/archderm.119.12.957. [DOI] [PubMed] [Google Scholar]
  9. Fleischmajer R., Perlish J. S., West W. P. Ultrastructure of cutaneous cellular infiltrates in scleroderma. Arch Dermatol. 1977 Dec;113(12):1661–1666. [PubMed] [Google Scholar]
  10. Gisslow M. T., McBride B. C. A rapid sensitive collagenase assay. Anal Biochem. 1975 Sep;68(1):70–78. doi: 10.1016/0003-2697(75)90680-6. [DOI] [PubMed] [Google Scholar]
  11. Goldring M. B., Sandell L. J., Stephenson M. L., Krane S. M. Immune interferon suppresses levels of procollagen mRNA and type II collagen synthesis in cultured human articular and costal chondrocytes. J Biol Chem. 1986 Jul 5;261(19):9049–9055. [PubMed] [Google Scholar]
  12. Granstein R. D., Margolis R., Mizel S. B., Sauder D. N. In vivo inflammatory activity of epidermal cell-derived thymocyte activating factor and recombinant interleukin 1 in the mouse. J Clin Invest. 1986 Mar;77(3):1020–1027. doi: 10.1172/JCI112354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guyre P. M., Morganelli P. M., Miller R. Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes. J Clin Invest. 1983 Jul;72(1):393–397. doi: 10.1172/JCI110980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jimenez S. A., Freundlich B., Rosenbloom J. Selective inhibition of human diploid fibroblast collagen synthesis by interferons. J Clin Invest. 1984 Sep;74(3):1112–1116. doi: 10.1172/JCI111480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jimenez S. A., McArthur W., Rosenbloom J. Inhibition of collagen synthesis by mononuclear cell supernates. J Exp Med. 1979 Dec 1;150(6):1421–1431. doi: 10.1084/jem.150.6.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kelley V. E., Fiers W., Strom T. B. Cloned human interferon-gamma, but not interferon-beta or -alpha, induces expression of HLA-DR determinants by fetal monocytes and myeloid leukemic cell lines. J Immunol. 1984 Jan;132(1):240–245. [PubMed] [Google Scholar]
  17. Korotzer T. I., Page R. C., Granger G. A., Rabinovitch P. S. Regulation of growth of human diploid fibroblasts by factors elaborated by activated lymphoid cells. J Cell Physiol. 1982 Jun;111(3):247–254. doi: 10.1002/jcp.1041110305. [DOI] [PubMed] [Google Scholar]
  18. Krane S. M., Dayer J. M., Simon L. S., Byrne M. S. Mononuclear cell-conditioned medium containing mononuclear cell factor (MCF), homologous with interleukin 1, stimulates collagen and fibronectin synthesis by adherent rheumatoid synovial cells: effects of prostaglandin E2 and indomethacin. Coll Relat Res. 1985 Mar;5(2):99–117. doi: 10.1016/s0174-173x(85)80033-9. [DOI] [PubMed] [Google Scholar]
  19. Le J., Prensky W., Yip Y. K., Chang Z., Hoffman T., Stevenson H. C., Balazs I., Sadlik J. R., Vilcek J. Activation of human monocyte cytotoxicity by natural and recombinant immune interferon. J Immunol. 1983 Dec;131(6):2821–2826. [PubMed] [Google Scholar]
  20. Leibovich S. J., Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed] [Google Scholar]
  21. Matsushima K., Bano M., Kidwell W. R., Oppenheim J. J. Interleukin 1 increases collagen type IV production by murine mammary epithelial cells. J Immunol. 1985 Feb;134(2):904–909. [PubMed] [Google Scholar]
  22. McArthur W., Derr K., Dixon M., Jimenez S. A., Rosenbloom J. Immune modulation of connective tissue functions: studies on the production of collagen synthesis inhibitory factor by populations of human peripheral blood mononuclear cells. Cell Immunol. 1982 Nov 15;74(1):126–139. doi: 10.1016/0008-8749(82)90013-2. [DOI] [PubMed] [Google Scholar]
  23. McCoy B. J., Person P., Cohen I. K. Collagen production and types in fibrous capsules around breast implants. Plast Reconstr Surg. 1984 Jun;73(6):924–927. doi: 10.1097/00006534-198406000-00012. [DOI] [PubMed] [Google Scholar]
  24. McCutcheon E. P., Evans J. M., Wibel F. H. A fabric pouch for maintaining transducer and catheter terminations. J Biomed Mater Res. 1982 Mar;16(2):105–115. doi: 10.1002/jbm.820160203. [DOI] [PubMed] [Google Scholar]
  25. Murphy G. F., Harrist T. J., Bhan A. K., Mihm M. C., Jr Distribution of cell surface antigens in histiocytosis X cells. Quantitative immunoelectron microscopy using monoclonal antibodies. Lab Invest. 1983 Jan;48(1):90–97. [PubMed] [Google Scholar]
  26. Murray H. W., Spitalny G. L., Nathan C. F. Activation of mouse peritoneal macrophages in vitro and in vivo by interferon-gamma. J Immunol. 1985 Mar;134(3):1619–1622. [PubMed] [Google Scholar]
  27. Murray J. C., Pollack S. V., Pinnell S. R. Keloids: a review. J Am Acad Dermatol. 1981 Apr;4(4):461–470. doi: 10.1016/s0190-9622(81)70048-3. [DOI] [PubMed] [Google Scholar]
  28. Perussia B., Dayton E. T., Fanning V., Thiagarajan P., Hoxie J., Trinchieri G. Immune interferon and leukocyte-conditioned medium induce normal and leukemic myeloid cells to differentiate along the monocytic pathway. J Exp Med. 1983 Dec 1;158(6):2058–2080. doi: 10.1084/jem.158.6.2058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Postlethwaite A. E., Smith G. N., Mainardi C. L., Seyer J. M., Kang A. H. Lymphocyte modulation of fibroblast function in vitro: stimulation and inhibition of collagen production by different effector molecules. J Immunol. 1984 May;132(5):2470–2477. [PubMed] [Google Scholar]
  30. 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]
  31. Schultz R. M., Chirigos M. A. Similarities among factors that render macrophages tumoricidal in lymphokine and interferon preparations. Cancer Res. 1978 Apr;38(4):1003–1007. [PubMed] [Google Scholar]
  32. Skoskiewicz M. J., Colvin R. B., Schneeberger E. E., Russell P. S. Widespread and selective induction of major histocompatibility complex-determined antigens in vivo by gamma interferon. J Exp Med. 1985 Nov 1;162(5):1645–1664. doi: 10.1084/jem.162.5.1645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Smahel J. Histology of the capsules causing constrictive fibrosis around breast implants. Br J Plast Surg. 1977 Oct;30(4):324–329. doi: 10.1016/0007-1226(77)90132-1. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Theeuwes F., Yum S. I. Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations. Ann Biomed Eng. 1976 Dec;4(4):343–353. doi: 10.1007/BF02584524. [DOI] [PubMed] [Google Scholar]
  36. Wahl S. M., Gately C. L. Modulation of fibroblast growth by a lymphokine of human T cell continuous T cell line origin. J Immunol. 1983 Mar;130(3):1226–1230. [PubMed] [Google Scholar]

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