Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Nov;86(5):1496–1502. doi: 10.1172/JCI114867

Neutral metalloproteinases produced by human mononuclear phagocytes. Enzyme profile, regulation, and expression during cellular development.

H G Welgus 1, E J Campbell 1, J D Cury 1, A Z Eisen 1, R M Senior 1, S M Wilhelm 1, G I Goldberg 1
PMCID: PMC296895  PMID: 2173721

Abstract

Mononuclear phagocytes are developmentally and functionally complex cells that play critical roles in extracellular matrix remodeling. We hypothesized that differentiated mononuclear phagocytes, typified by alveolar macrophages, use a spectrum of metalloproteinases to degrade various matrix macromolecules. To test this hypothesis, we have evaluated synthesis and secretion of four metalloproteinases (interstitial collagenase, stromelysin, 72-kD type IV collagenase, and 92-kD type IV collagenase) by human mononuclear phagocytes with regard to (a) the effect of cellular differentiation, (b) regulation of secretion, and (c) comparisons/contrasts with a prototype metalloproteinase-secretory cell, the human fibroblast. We found that regulated secretion of greater quantities and a wider spectrum of metalloenzymes correlated with a more differentiated cellular phenotype. As extreme examples, the 92-kD type IV collagenase was released by peripheral blood monocytes and uninduced U937 monocyte-like cells, whereas stromelysin was secreted only by lipopolysaccharide-stimulated alveolar macrophages. Macrophage production of interstitial collagenase, stromelysin, and 72-kD type IV collagenase was approximately 20%, 10%, and 1-2%, respectively, of that from equal numbers of fibroblasts; secretion of the 92-kD type IV collagenase was not shared by fibroblasts. This work confirms the potential of macrophages to directly degrade extracellular matrix via secreted metalloproteinases in a manner that differs both qualitatively and quantitatively from that of fibroblasts. Moreover, varying regulation of metalloenzyme synthesis, evidenced by distinct patterns of basal and stimulated secretion during differentiation, can be studied at a molecular level in this model system.

Full text

PDF
1496

Images in this article

1498Image
on p.1498
1498Image
on p.1498
1498Image
on p.1498
1498Image
on p.1498
1499Image
on p.1499
1499Image
on p.1499
1499Image
on p.1499
1500Image
on p.1500

Selected References

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

  1. Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. doi: 10.1016/0092-8674(87)90611-8. [DOI] [PubMed] [Google Scholar]
  2. Birkedal-Hansen H., Taylor R. E. Detergent-activation of latent collagenase and resolution of its component molecules. Biochem Biophys Res Commun. 1982 Aug 31;107(4):1173–1178. doi: 10.1016/s0006-291x(82)80120-4. [DOI] [PubMed] [Google Scholar]
  3. Brinckerhoff C. E., Gross R. H., Nagase H., Sheldon L., Jackson R. C., Harris E. D., Jr Increased level of translatable collagenase messenger ribonucleic acid in rabbit synovial fibroblasts treated with phorbol myristate acetate or crystals of monosodium urate monohydrate. Biochemistry. 1982 May 25;21(11):2674–2679. doi: 10.1021/bi00540a015. [DOI] [PubMed] [Google Scholar]
  4. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  5. Campbell E. J., Cury J. D., Lazarus C. J., Welgus H. G. Monocyte procollagenase and tissue inhibitor of metalloproteinases. Identification, characterization, and regulation of secretion. J Biol Chem. 1987 Nov 25;262(33):15862–15868. [PubMed] [Google Scholar]
  6. Campbell E. J., Silverman E. K., Campbell M. A. Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity. J Immunol. 1989 Nov 1;143(9):2961–2968. [PubMed] [Google Scholar]
  7. Cawston T. E., Murphy G., Mercer E., Galloway W. A., Hazleman B. L., Reynolds J. J. The interaction of purified rabbit bone collagenase with purified rabbit bone metalloproteinase inhibitor. Biochem J. 1983 May 1;211(2):313–318. doi: 10.1042/bj2110313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chapman H. A., Jr, Stone O. L., Vavrin Z. Degradation of fibrin and elastin by intact human alveolar macrophages in vitro. Characterization of a plasminogen activator and its role in matrix degradation. J Clin Invest. 1984 Mar;73(3):806–815. doi: 10.1172/JCI111275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Collier I. E., Smith J., Kronberger A., Bauer E. A., Wilhelm S. M., Eisen A. Z., Goldberg G. I. The structure of the human skin fibroblast collagenase gene. J Biol Chem. 1988 Aug 5;263(22):10711–10713. [PubMed] [Google Scholar]
  11. Collier I. E., Wilhelm S. M., Eisen A. Z., Marmer B. L., Grant G. A., Seltzer J. L., Kronberger A., He C. S., Bauer E. A., Goldberg G. I. H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J Biol Chem. 1988 May 15;263(14):6579–6587. [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. Fini M. E., Plucinska I. M., Mayer A. S., Gross R. H., Brinckerhoff C. E. A gene for rabbit synovial cell collagenase: member of a family of metalloproteinases that degrade the connective tissue matrix. Biochemistry. 1987 Sep 22;26(19):6156–6165. doi: 10.1021/bi00393a032. [DOI] [PubMed] [Google Scholar]
  18. Garbisa S., Ballin M., Daga-Gordini D., Fastelli G., Naturale M., Negro A., Semenzato G., Liotta L. A. Transient expression of type IV collagenolytic metalloproteinase by human mononuclear phagocytes. J Biol Chem. 1986 Feb 15;261(5):2369–2375. [PubMed] [Google Scholar]
  19. 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]
  20. Hasty K. A., Hibbs M. S., Kang A. H., Mainardi C. L. Heterogeneity among human collagenases demonstrated by monoclonal antibody that selectively recognizes and inhibits human neutrophil collagenase. J Exp Med. 1984 May 1;159(5):1455–1463. doi: 10.1084/jem.159.5.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hasty K. A., Hibbs M. S., Kang A. H., Mainardi C. L. Secreted forms of human neutrophil collagenase. J Biol Chem. 1986 Apr 25;261(12):5645–5650. [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Laskey R. A., Mills A. D. Quantitative film detection of 3H and 14C in polyacrylamide gels by fluorography. Eur J Biochem. 1975 Aug 15;56(2):335–341. doi: 10.1111/j.1432-1033.1975.tb02238.x. [DOI] [PubMed] [Google Scholar]
  25. Mainardi C. L., Dixit S. N., Kang A. H. Degradation of type IV (basement membrane) collagen by a proteinase isolated from human polymorphonuclear leukocyte granules. J Biol Chem. 1980 Jun 10;255(11):5435–5441. [PubMed] [Google Scholar]
  26. Mainardi C. L., Hibbs M. S., Hasty K. A., Seyer J. M. Purification of a type V collagen degrading metalloproteinase from rabbit alveolar macrophages. Coll Relat Res. 1984 Dec;4(6):479–492. doi: 10.1016/s0174-173x(84)80014-x. [DOI] [PubMed] [Google Scholar]
  27. Pipoly D. J., Crouch E. C. Degradation of native type IV procollagen by human neutrophil elastase. Implications for leukocyte-mediated degradation of basement membranes. Biochemistry. 1987 Sep 8;26(18):5748–5754. doi: 10.1021/bi00392a025. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Sanderson R. J., Shepperdson R. T., Vatter A. E., Talmage D. W. Isolation and enumeration of peripheral blood monocytes. J Immunol. 1977 Apr;118(4):1409–1414. [PubMed] [Google Scholar]
  30. Seckinger P., Isaaz S., Dayer J. M. A human inhibitor of tumor necrosis factor alpha. J Exp Med. 1988 Apr 1;167(4):1511–1516. doi: 10.1084/jem.167.4.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sedmak J. J., Grossberg S. E. A rapid, sensitive, and versatile assay for protein using Coomassie brilliant blue G250. Anal Biochem. 1977 May 1;79(1-2):544–552. doi: 10.1016/0003-2697(77)90428-6. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. Welgus H. G., Jeffrey J. J., Eisen A. Z., Roswit W. T., Stricklin G. P. Human skin fibroblast collagenase: interaction with substrate and inhibitor. Coll Relat Res. 1985 Mar;5(2):167–179. doi: 10.1016/s0174-173x(85)80038-8. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Whitham S. E., Murphy G., Angel P., Rahmsdorf H. J., Smith B. J., Lyons A., Harris T. J., Reynolds J. J., Herrlich P., Docherty A. J. Comparison of human stromelysin and collagenase by cloning and sequence analysis. Biochem J. 1986 Dec 15;240(3):913–916. doi: 10.1042/bj2400913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. 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]
  41. Wilhelm S. M., Eisen A. Z., Teter M., Clark S. D., Kronberger A., Goldberg G. Human fibroblast collagenase: glycosylation and tissue-specific levels of enzyme synthesis. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3756–3760. doi: 10.1073/pnas.83.11.3756. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES