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. 1990 Oct;86(4):1204–1210. doi: 10.1172/JCI114826

Immune modulation of metalloproteinase production in human macrophages. Selective pretranslational suppression of interstitial collagenase and stromelysin biosynthesis by interferon-gamma.

S D Shapiro 1, E J Campbell 1, D K Kobayashi 1, H G Welgus 1
PMCID: PMC296850  PMID: 2170447

Abstract

Interferon-gamma (IFN-gamma) is a lymphokine that activates mononuclear phagocytes. To test the hypothesis that IFN-gamma might have important effects upon the ability of human mononuclear phagocytes to degrade extracellular matrix, we have studied the action of this cytokine on the production of metalloproteinases and the counterregulatory tissue inhibitor of metalloproteinases (TIMP) by the human alveolar macrophage. We have found that IFN-gamma potently and selectively suppresses the lipopolysaccharide-induced production of two metalloproteinases--interstitial collagenase and stromelysin--by 50-90% at doses greater than or equal to 10 U/ml. The synthesis of TIMP and 92-kD type IV collagenase was also diminished by IFN-gamma, but these responses required 50- to 100-fold higher concentrations of the cytokine. All doses of IFN-gamma increased total and secreted protein synthesis slightly, indicating a highly specific effect on metalloenzyme biosynthesis. Inhibition of metalloproteinase expression occurred at a pretranslational level, as evidenced by parallel reductions in enzyme biosynthesis and collagenase-specific steady-state mRNA levels. Interestingly, the effect of IFN-gamma on metalloenzyme production was not readily reversible. Therefore, while IFN-gamma activates the macrophage and renders it tumoricidal, this enhanced function appears to be attained at the expense of the cell's capacity to degrade extracellular matrix.

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Selected References

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

  1. Adams D. O., Hamilton T. A. Molecular transductional mechanisms by which IFN gamma and other signals regulate macrophage development. Immunol Rev. 1987 Jun;97:5–27. doi: 10.1111/j.1600-065x.1987.tb00514.x. [DOI] [PubMed] [Google Scholar]
  2. Albin R. J., Senior R. M., Welgus H. G., Connolly N. L., Campbell E. J. Human alveolar macrophages secrete an inhibitor of metalloproteinase elastase. Am Rev Respir Dis. 1987 Jun;135(6):1281–1285. doi: 10.1164/arrd.1987.135.6.1281. [DOI] [PubMed] [Google Scholar]
  3. Bauer E. A., Cooper T. W., Huang J. S., Altman J., Deuel T. F. Stimulation of in vitro human skin collagenase expression by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4132–4136. doi: 10.1073/pnas.82.12.4132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brenner D. A., O'Hara M., Angel P., Chojkier M., Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989 Feb 16;337(6208):661–663. doi: 10.1038/337661a0. [DOI] [PubMed] [Google Scholar]
  5. Carmichael D. F., Sommer A., Thompson R. C., Anderson D. C., Smith C. G., Welgus H. G., Stricklin G. P. Primary structure and cDNA cloning of human fibroblast collagenase inhibitor. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2407–2411. doi: 10.1073/pnas.83.8.2407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Celada A., Allen R., Esparza I., Gray P. W., Schreiber R. D. Demonstration and partial characterization of the interferon-gamma receptor on human mononuclear phagocytes. J Clin Invest. 1985 Dec;76(6):2196–2205. doi: 10.1172/JCI112228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Celada A., Gray P. W., Rinderknecht E., Schreiber R. D. Evidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity. J Exp Med. 1984 Jul 1;160(1):55–74. doi: 10.1084/jem.160.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chin J. R., Murphy G., Werb Z. Stromelysin, a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization, and substrates. J Biol Chem. 1985 Oct 5;260(22):12367–12376. [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Collart M. A., Belin D., Vassalli J. D., de Kossodo S., Vassalli P. Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J Exp Med. 1986 Dec 1;164(6):2113–2118. doi: 10.1084/jem.164.6.2113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cooper T. W., Bauer E. A., Eisen A. Z. Enzyme-linked immunosorbent assay for human skin collagenase. Coll Relat Res. 1983 May;3(3):205–215. doi: 10.1016/s0174-173x(83)80004-1. [DOI] [PubMed] [Google Scholar]
  12. Cury J. D., Campbell E. J., Lazarus C. J., Albin R. J., Welgus H. G. Selective up-regulation of human alveolar macrophage collagenase production by lipopolysaccharide and comparison to collagenase production by fibroblasts. J Immunol. 1988 Dec 15;141(12):4306–4312. [PubMed] [Google Scholar]
  13. Dayer J. M., Beutler B., Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985 Dec 1;162(6):2163–2168. doi: 10.1084/jem.162.6.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dayer J. M., Bréard J., Chess L., Krane S. M. Participation of monocyte-macrophages and lymphocytes in the production of a factor that stimulates collagenase and prostaglandin release by rheumatoid synovial cells. J Clin Invest. 1979 Nov;64(5):1386–1392. doi: 10.1172/JCI109596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dayer J. M., de Rochemonteix B., Burrus B., Demczuk S., Dinarello C. A. Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells. J Clin Invest. 1986 Feb;77(2):645–648. doi: 10.1172/JCI112350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fan X. D., Goldberg M., Bloom B. R. Interferon-gamma-induced transcriptional activation is mediated by protein kinase C. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5122–5125. doi: 10.1073/pnas.85.14.5122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fertsch D., Vogel S. N. Recombinant interferons increase macrophage Fc receptor capacity. J Immunol. 1984 May;132(5):2436–2439. [PubMed] [Google Scholar]
  18. Goldberg G. I., Wilhelm S. M., Kronberger A., Bauer E. A., Grant G. A., Eisen A. Z. Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. J Biol Chem. 1986 May 15;261(14):6600–6605. [PubMed] [Google Scholar]
  19. Harris E. D., Jr, Welgus H. G., Krane S. M. Regulation of the mammalian collagenases. Coll Relat Res. 1984 Dec;4(6):493–512. doi: 10.1016/s0174-173x(84)80015-1. [DOI] [PubMed] [Google Scholar]
  20. Hibbs M. S., Hoidal J. R., Kang A. H. Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages. J Clin Invest. 1987 Dec;80(6):1644–1650. doi: 10.1172/JCI113253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. King J., Laemmli U. K. Polypeptides of the tail fibres of bacteriophage T4. J Mol Biol. 1971 Dec 28;62(3):465–477. doi: 10.1016/0022-2836(71)90148-3. [DOI] [PubMed] [Google Scholar]
  22. Prpic V., Yu S. F., Figueiredo F., Hollenbach P. W., Gawdi G., Herman B., Uhing R. J., Adams D. O. Role of Na+/H+ exchange by interferon-gamma in enhanced expression of JE and I-A beta genes. Science. 1989 Apr 28;244(4903):469–471. doi: 10.1126/science.2541500. [DOI] [PubMed] [Google Scholar]
  23. Salo T., Turpeenniemi-Hujanen T., Tryggvason K. Tumor-promoting phorbol esters and cell proliferation stimulate secretion of basement membrane (type IV) collagen-degrading metalloproteinase by human fibroblasts. J Biol Chem. 1985 Jul 15;260(14):8526–8531. [PubMed] [Google Scholar]
  24. Senior R. M., Campbell E. J., Landis J. A., Cox F. R., Kuhn C., Koren H. S. Elastase of U-937 monocytelike cells. Comparisons with elastases derived from human monocytes and neutrophils and murine macrophagelike cells. J Clin Invest. 1982 Feb;69(2):384–393. doi: 10.1172/JCI110462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Senior R. M., Connolly N. L., Cury J. D., Welgus H. G., Campbell E. J. Elastin degradation by human alveolar macrophages. A prominent role of metalloproteinase activity. Am Rev Respir Dis. 1989 May;139(5):1251–1256. doi: 10.1164/ajrccm/139.5.1251. [DOI] [PubMed] [Google Scholar]
  26. Steeg P. S., Johnson H. M., Oppenheim J. J. Regulation of murine macrophage Ia antigen expression by an immune interferon-like lymphokine: inhibitory effect of endotoxin. J Immunol. 1982 Dec;129(6):2402–2406. [PubMed] [Google Scholar]
  27. Stricklin G. P., Bauer E. A., Jeffrey J. J., Eisen A. Z. Human skin collagenase: isolation of precursor and active forms from both fibroblast and organ cultures. Biochemistry. 1977 Apr 19;16(8):1607–1615. doi: 10.1021/bi00627a013. [DOI] [PubMed] [Google Scholar]
  28. Stricklin G. P., Welgus H. G. Human skin fibroblast collagenase inhibitor. Purification and biochemical characterization. J Biol Chem. 1983 Oct 25;258(20):12252–12258. [PubMed] [Google Scholar]
  29. Ucla C., Roux-Lombard P., Fey S., Dayer J. M., Mach B. Interferon gamma drastically modifies the regulation of interleukin 1 genes by endotoxin in U937 cells. J Clin Invest. 1990 Jan;85(1):185–191. doi: 10.1172/JCI114411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Unanue E. R. Antigen-presenting function of the macrophage. Annu Rev Immunol. 1984;2:395–428. doi: 10.1146/annurev.iy.02.040184.002143. [DOI] [PubMed] [Google Scholar]
  31. Wallach D., Fellous M., Revel M. Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells. Nature. 1982 Oct 28;299(5886):833–836. doi: 10.1038/299833a0. [DOI] [PubMed] [Google Scholar]
  32. Welgus H. G., Campbell E. J., Bar-Shavit Z., Senior R. M., Teitelbaum S. L. Human alveolar macrophages produce a fibroblast-like collagenase and collagenase inhibitor. J Clin Invest. 1985 Jul;76(1):219–224. doi: 10.1172/JCI111949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Welgus H. G., Connolly N. L., Senior R. M. 12-o-Tetradecanoyl-phorbol-13-acetate-differentiated U937 cells express a macrophage-like profile of neutral proteinases. High levels of secreted collagenase and collagenase inhibitor accompany low levels of intracellular elastase and cathepsin G. J Clin Invest. 1986 May;77(5):1675–1681. doi: 10.1172/JCI112485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Welgus H. G., Stricklin G. P. Human skin fibroblast collagenase inhibitor. Comparative studies in human connective tissues, serum, and amniotic fluid. J Biol Chem. 1983 Oct 25;258(20):12259–12264. [PubMed] [Google Scholar]
  35. Wilhelm S. M., Collier I. E., Kronberger A., Eisen A. Z., Marmer B. L., Grant G. A., Bauer E. A., Goldberg G. I. Human skin fibroblast stromelysin: structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6725–6729. doi: 10.1073/pnas.84.19.6725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wilhelm S. M., Collier I. E., Marmer B. L., Eisen A. Z., Grant G. A., Goldberg G. I. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem. 1989 Oct 15;264(29):17213–17221. [PubMed] [Google Scholar]

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