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. 1987 Feb 1;165(2):320–339. doi: 10.1084/jem.165.2.320

Plasminogen activator-specific inhibitors produced by human monocytes/macrophages

PMCID: PMC2188521  PMID: 2434595

Abstract

Human monocytes/macrophages produce plasminogen activator-specific inhibitors (PAIs) that form covalent complexes with urokinase-type plasminogen activator (uPA). We have characterized two functionally and antigenically related forms of PAIs produced by resting and phorbol myristate acetate (PMA)-treated U 937 cells: an Mr 40,000 form, presumably nonglycosylated, with a pI of 5.2, that is constitutively synthetized by these cells and that remains predominantly intracellular; a PMA-induced form of heterogeneous Mr (50,000-65,000) with a pI of 4.7, that is preferentially secreted; this PAI is glycosylated with terminal sialic acid residue(s). Biosynthetic labeling experiments demonstrated that both PAIs are synthetized by U 937 cells. They are inactivated upon treatment with propanol, heat, and acid; the covalent and equimolar complexes formed between these PAIs and 125I-uPA are dissociated by ammonium hydroxide, suggesting that the PAIs are linked to uPA via an ester bond. Human peripheral blood monocytes/macrophages also produce the two forms of PAI. These PAIs are clearly different from the main plasma protease inhibitors and they are both antigenically related to the PAI-2 characterized in human placenta.

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Selected References

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  1. Astedt B., Lecander I., Brodin T., Lundblad A., Löw K. Purification of a specific placental plasminogen activator inhibitor by monoclonal antibody and its complex formation with plasminogen activator. Thromb Haemost. 1985 Feb 18;53(1):122–125. [PubMed] [Google Scholar]
  2. Baker J. B., Low D. A., Simmer R. L., Cunningham D. D. Protease-nexin: a cellular component that links thrombin and plasminogen activator and mediates their binding to cells. Cell. 1980 Aug;21(1):37–45. doi: 10.1016/0092-8674(80)90112-9. [DOI] [PubMed] [Google Scholar]
  3. Beatty K., Bieth J., Travis J. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem. 1980 May 10;255(9):3931–3934. [PubMed] [Google Scholar]
  4. Busso N., Belin D., Failly-Crépin C., Vassalli J. D. Plasminogen activators and their inhibitors in a human mammary cell line (HBL-100). Modulation by glucocorticoids. J Biol Chem. 1986 Jul 15;261(20):9309–9315. [PubMed] [Google Scholar]
  5. Chapman H. A., Jr, Stone O. L. Characterization of a macrophage-derived plasminogen-activator inhibitor. Similarities with placental urokinase inhibitor. Biochem J. 1985 Aug 15;230(1):109–116. doi: 10.1042/bj2300109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chapman H. A., Jr, Vavrin Z., Hibbs J. B., Jr Macrophage fibrinolytic activity: identification of two pathways of plasmin formation by intact cells and of a plasminogen activator inhibitor. Cell. 1982 Mar;28(3):653–662. doi: 10.1016/0092-8674(82)90220-3. [DOI] [PubMed] [Google Scholar]
  7. Christensen U., Holmberg L., Bladh B., Astedt B. Kinetics of the reaction between urokinase and an inhibitor of fibrinolysis from placental tissue. Thromb Haemost. 1982 Aug 24;48(1):24–26. [PubMed] [Google Scholar]
  8. 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]
  9. Deutsch D. G., Mertz E. T. Plasminogen: purification from human plasma by affinity chromatography. Science. 1970 Dec 4;170(3962):1095–1096. doi: 10.1126/science.170.3962.1095. [DOI] [PubMed] [Google Scholar]
  10. Eaton D. L., Scott R. W., Baker J. B. Purification of human fibroblast urokinase proenzyme and analysis of its regulation by proteases and protease nexin. J Biol Chem. 1984 May 25;259(10):6241–6247. [PubMed] [Google Scholar]
  11. Erickson L. A., Ginsberg M. H., Loskutoff D. J. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest. 1984 Oct;74(4):1465–1472. doi: 10.1172/JCI111559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Erickson L. A., Hekman C. M., Loskutoff D. J. The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8710–8714. doi: 10.1073/pnas.82.24.8710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Golder J. P., Stephens R. W. Minactivin: a human monocyte product which specifically inactivates urokinase-type plasminogen activators. Eur J Biochem. 1983 Nov 15;136(3):517–522. doi: 10.1111/j.1432-1033.1983.tb07771.x. [DOI] [PubMed] [Google Scholar]
  14. Gordon S., Unkeless J. C., Cohn Z. A. Induction of macrophage plasminogen activator by endotoxin stimulation and phagocytosis: evidence for a two-stage process. J Exp Med. 1974 Oct 1;140(4):995–1010. doi: 10.1084/jem.140.4.995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Holmberg L., Lecander I., Persson B., Astedt B. An inhibitor from placenta specifically binds urokinase and inhibits plasminogen activator released from ovarian carcinoma in tissue culture. Biochim Biophys Acta. 1978 Nov 15;544(1):128–137. doi: 10.1016/0304-4165(78)90216-7. [DOI] [PubMed] [Google Scholar]
  16. Kawano T., Morimoto K., Uemura Y. Partial purification and properties of urokinase inhibitor from human placenta. J Biochem. 1970 Mar;67(3):333–342. doi: 10.1093/oxfordjournals.jbchem.a129257. [DOI] [PubMed] [Google Scholar]
  17. Klimetzek V., Sorg C. The production of fibrinolysis inhibitors as a parameter of the activation state in murine macrophages. Eur J Immunol. 1979 Aug;9(8):613–619. doi: 10.1002/eji.1830090808. [DOI] [PubMed] [Google Scholar]
  18. Kopitar M., Rozman B., Babnik J., Turk V., Mullins D. E., Wun T. C. Human leucocyte urokinase inhibitor--purification, characterization and comparative studies against different plasminogen activators. Thromb Haemost. 1985 Dec 17;54(4):750–755. [PubMed] [Google Scholar]
  19. Kruithof E. K., Tran-Thang C., Ransijn A., Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood. 1984 Oct;64(4):907–913. [PubMed] [Google Scholar]
  20. Kruithof E. K., Vassalli J. D., Schleuning W. D., Mattaliano R. J., Bachmann F. Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937. J Biol Chem. 1986 Aug 25;261(24):11207–11213. [PubMed] [Google Scholar]
  21. Lecander I., Astedt B. Isolation of a new specific plasminogen activator inhibitor from pregnancy plasma. Br J Haematol. 1986 Feb;62(2):221–228. doi: 10.1111/j.1365-2141.1986.tb02925.x. [DOI] [PubMed] [Google Scholar]
  22. Lemaire G., Drapier J. C., Petit J. F. Importance, localization and functional properties of the cell-associated form of plasminogen activator in mouse peritoneal macrophages. Biochim Biophys Acta. 1983 Feb 22;755(3):332–343. doi: 10.1016/0304-4165(83)90235-0. [DOI] [PubMed] [Google Scholar]
  23. Loskutoff D. J., van Mourik J. A., Erickson L. A., Lawrence D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci U S A. 1983 May;80(10):2956–2960. doi: 10.1073/pnas.80.10.2956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Low D. A., Baker J. B., Koonce W. C., Cunningham D. D. Released protease-nexin regulates cellular binding, internalization, and degradation of serine proteases. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2340–2344. doi: 10.1073/pnas.78.4.2340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nielsen L. S., Andreasen P. A., Grøndahl-Hansen J., Skriver L., Danø K. Plasminogen activators catalyse conversion of inhibitor from fibrosarcoma cells to an inactive form with a lower apparent molecular mass. FEBS Lett. 1986 Feb 17;196(2):269–273. doi: 10.1016/0014-5793(86)80261-7. [DOI] [PubMed] [Google Scholar]
  26. Nilsson K., Forsbeck K., Gidlund M., Sundström C., Tötterman T., Sällström J., Venge P. Surface characteristics of the U-937 human histiocytic lymphoma cell line: specific changes during inducible morphologic and functional differentiation in vitro. Haematol Blood Transfus. 1981;26:215–221. doi: 10.1007/978-3-642-67984-1_35. [DOI] [PubMed] [Google Scholar]
  27. Perlmutter D. H., Cole F. S., Kilbridge P., Rossing T. H., Colten H. R. Expression of the alpha 1-proteinase inhibitor gene in human monocytes and macrophages. Proc Natl Acad Sci U S A. 1985 Feb;82(3):795–799. doi: 10.1073/pnas.82.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Remold-O'Donnell E. A fast-acting elastase inhibitor in human monocytes. J Exp Med. 1985 Dec 1;162(6):2142–2155. doi: 10.1084/jem.162.6.2142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rijken D. C., Juhan-Vague I., Collen D. Complexes between tissue-type plasminogen activator and proteinase inhibitors in human plasma, identified with an immunoradiometric assay. J Lab Clin Med. 1983 Feb;101(2):285–294. [PubMed] [Google Scholar]
  30. Saksela O., Hovi T., Vaheri A. Urokinase-type plasminogen activator and its inhibitor secreted by cultured human monocyte-macrophages. J Cell Physiol. 1985 Jan;122(1):125–132. doi: 10.1002/jcp.1041220119. [DOI] [PubMed] [Google Scholar]
  31. Scott R. W., Baker J. B. Purification of human protease nexin. J Biol Chem. 1983 Sep 10;258(17):10439–10444. [PubMed] [Google Scholar]
  32. Scott R. W., Bergman B. L., Bajpai A., Hersh R. T., Rodriguez H., Jones B. N., Barreda C., Watts S., Baker J. B. Protease nexin. Properties and a modified purification procedure. J Biol Chem. 1985 Jun 10;260(11):7029–7034. [PubMed] [Google Scholar]
  33. Thorsen S., Philips M. Isolation of tissue-type plasminogen activator-inhibitor complexes from human plasma. Evidence for a rapid plasminogen activator inhibitor. Biochim Biophys Acta. 1984 Nov 6;802(1):111–118. doi: 10.1016/0304-4165(84)90040-0. [DOI] [PubMed] [Google Scholar]
  34. Travis J., Salvesen G. S. Human plasma proteinase inhibitors. Annu Rev Biochem. 1983;52:655–709. doi: 10.1146/annurev.bi.52.070183.003255. [DOI] [PubMed] [Google Scholar]
  35. Unkeless J. C., Gordon S., Reich E. Secretion of plasminogen activator by stimulated macrophages. J Exp Med. 1974 Apr 1;139(4):834–850. doi: 10.1084/jem.139.4.834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Vassalli J. D., Dayer J. M., Wohlwend A., Belin D. Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages. J Exp Med. 1984 Jun 1;159(6):1653–1668. doi: 10.1084/jem.159.6.1653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vassalli J. D., Hamilton J., Reich E. Macrophage plasminogen activator: induction by concanavalin A and phorbol myristate acetate. Cell. 1977 Jul;11(3):695–705. doi: 10.1016/0092-8674(77)90086-1. [DOI] [PubMed] [Google Scholar]
  38. Vassalli J. D., Hamilton J., Reich E. Macrophage plasminogen activator: modulation of enzyme production by anti-inflammatory steroids, mitotic inhibitors, and cyclic nucleotides. Cell. 1976 Jun;8(2):271–281. doi: 10.1016/0092-8674(76)90011-8. [DOI] [PubMed] [Google Scholar]
  39. Vassalli J. D., Reich E. Macrophage plasminogen activator: induction by products of activated lymphoid cells. J Exp Med. 1977 Feb 1;145(2):429–437. doi: 10.1084/jem.145.2.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Waller E. K., Schleuning W. D., Reich E. Complex-formation and inhibition of urokinase by blood plasma proteins. Biochem J. 1983 Oct 1;215(1):123–131. doi: 10.1042/bj2150123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wiman B., Chmielewska J., Rånby M. Inactivation of tissue plasminogen activator in plasma. Demonstration of a complex with a new rapid inhibitor. J Biol Chem. 1984 Mar 25;259(6):3644–3647. [PubMed] [Google Scholar]
  42. van Mourik J. A., Lawrence D. A., Loskutoff D. J. Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J Biol Chem. 1984 Dec 10;259(23):14914–14921. [PubMed] [Google Scholar]

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