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. 1988 Jun;81(6):1774–1780. doi: 10.1172/JCI113519

Elastase regulates the synthesis of its inhibitor, alpha 1-proteinase inhibitor, and exaggerates the defect in homozygous PiZZ alpha 1 PI deficiency.

D H Perlmutter 1, J Travis 1, P I Punsal 1
PMCID: PMC442624  PMID: 3260245

Abstract

The net balance of neutrophil elastase, an enzyme that degrades many components of the extracellular matrix, and its inhibitor, alpha-1-proteinase inhibitor (alpha 1 PI), is thought to be a critical determinant in the development of destructive lung disease, especially in individuals with homozygous alpha 1 PI deficiency. Synthesis and secretion of alpha 1 PI has been recently demonstrated in cells of mononuclear phagocyte lineage, including peripheral blood monocytes and tissue macrophages. In this study we show that alpha 1 PI gene expression in human monocytes and bronchoalveolar macrophages is affected by a novel mechanism, whereby elastase directly regulates the synthesis of its inhibitor. In nanomolar concentrations, neutrophil or pancreatic elastase mediates a dose- and time-dependent increase in steady state levels of alpha 1 PI mRNA and in the rate of synthesis of alpha 1 PI in human monocytes and bronchoalveolar macrophages. Antisera to neutrophil elastase or pretreatment of elastase with the serine proteinase inhibitor diisopropylfluorophosphate abrogates the effect of elastase on alpha 1 PI expression. Elastase also stimulates the synthesis of alpha 1 PI in monocytes from homozygous PiZZ alpha 1 PI-deficient individuals, but has no effect on the rate of secretion; hence, the enzyme mediates an effect on alpha 1 PI that increases the intracellular accumulation of inhibitor and exaggerates the intrinsic defect in secretion of alpha 1 PI that characterizes the homozygous PiZZ alpha 1 PI deficiency.

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Selected References

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

  1. Banda M. J., Clark E. J., Werb Z. Limited proteolysis by macrophage elastase inactivates human alpha 1-proteinase inhibitor. J Exp Med. 1980 Dec 1;152(6):1563–1570. doi: 10.1084/jem.152.6.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barbey-Morel C., Pierce J. A., Campbell E. J., Perlmutter D. H. Lipopolysaccharide modulates the expression of alpha 1 proteinase inhibitor and other serine proteinase inhibitors in human monocytes and macrophages. J Exp Med. 1987 Oct 1;166(4):1041–1054. doi: 10.1084/jem.166.4.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baugh R. J., Travis J. Human leukocyte granule elastase: rapid isolation and characterization. Biochemistry. 1976 Feb 24;15(4):836–841. doi: 10.1021/bi00649a017. [DOI] [PubMed] [Google Scholar]
  4. Beatty K., Robertie P., Senior R. M., Travis J. Determination of oxidized alpha-1-proteinase inhibitor in serum. J Lab Clin Med. 1982 Aug;100(2):186–192. [PubMed] [Google Scholar]
  5. Bensa J. C., Reboul A., Colomb M. G. Biosynthesis in vitro of complement subcomponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes. Biochem J. 1983 Nov 15;216(2):385–392. doi: 10.1042/bj2160385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bing D. H., Andrews J. M., Morris K. M., Cole E., Irish V. Purification of subcomponents Clq, Cl(-)r and Cl(-)s of the first component of complement from Cohn Fraction I by affinity chromatography. Prep Biochem. 1980;10(3):269–296. doi: 10.1080/10826068009412829. [DOI] [PubMed] [Google Scholar]
  7. Carrell R. W. alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage. J Clin Invest. 1986 Dec;78(6):1427–1431. doi: 10.1172/JCI112731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Ciliberto G., Dente L., Cortese R. Cell-specific expression of a transfected human alpha 1-antitrypsin gene. Cell. 1985 Jun;41(2):531–540. doi: 10.1016/s0092-8674(85)80026-x. [DOI] [PubMed] [Google Scholar]
  10. Cole F. S., Auerbach H. S., Goldberger G., Colten H. R. Tissue-specific pretranslational regulation of complement production in human mononuclear phagocytes. J Immunol. 1985 Apr;134(4):2610–2616. [PubMed] [Google Scholar]
  11. Cole F. S., Matthews W. J., Jr, Rossing T. H., Gash D. J., Lichtenberg N. A., Pennington J. E. Complement biosynthesis by human bronchoalveolar macrophages. Clin Immunol Immunopathol. 1983 May;27(2):153–159. doi: 10.1016/0090-1229(83)90065-x. [DOI] [PubMed] [Google Scholar]
  12. Darlington G. J., Wilson D. R., Lachman L. B. Monocyte-conditioned medium, interleukin-1, and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro. J Cell Biol. 1986 Sep;103(3):787–793. doi: 10.1083/jcb.103.3.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dickson I., Alper C. A. Changes in serum proteinase inhibitor levels following bone surgery. Clin Chim Acta. 1974 Aug 20;54(3):381–385. doi: 10.1016/0009-8981(74)90257-5. [DOI] [PubMed] [Google Scholar]
  14. Einstein L. P., Schneeberger E. E., Colten H. R. Synthesis of the second component of complement by long-term primary cultures of human monocytes. J Exp Med. 1976 Jan 1;143(1):114–126. doi: 10.1084/jem.143.1.114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Foreman R. C., Judah J. D., Colman A. Xenopus oocytes can synthesise but do not secrete the Z variant of human alpha 1-antitrypsin. FEBS Lett. 1984 Mar 12;168(1):84–88. doi: 10.1016/0014-5793(84)80211-2. [DOI] [PubMed] [Google Scholar]
  16. Garver R. I., Jr, Mornex J. F., Nukiwa T., Brantly M., Courtney M., LeCocq J. P., Crystal R. G. Alpha 1-antitrypsin deficiency and emphysema caused by homozygous inheritance of non-expressing alpha 1-antitrypsin genes. N Engl J Med. 1986 Mar 20;314(12):762–766. doi: 10.1056/NEJM198603203141207. [DOI] [PubMed] [Google Scholar]
  17. Gelehrter T. D., Sznycer-Laszuk R. Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells. J Clin Invest. 1986 Jan;77(1):165–169. doi: 10.1172/JCI112271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Graves C. B., Munns T. W., Carlisle T. L., Grant G. A., Strauss A. W. Induction of prothrombin synthesis by prothrombin fragments. Proc Natl Acad Sci U S A. 1981 Aug;78(8):4772–4776. doi: 10.1073/pnas.78.8.4772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Graves C. B., Munns T. W., Willingham A. K., Strauss A. W. Rat factor X is synthesized as a single chain precursor inducible by prothrombin fragments. J Biol Chem. 1982 Nov 10;257(21):13108–13113. [PubMed] [Google Scholar]
  20. Hovi T., Mosher D., Vaheri A. Cultured human monocytes synthesize and secrete alpha2-macroglobulin. J Exp Med. 1977 Jun 1;145(6):1580–1589. doi: 10.1084/jem.145.6.1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Johnson D. A., Barrett A. J., Mason R. W. Cathepsin L inactivates alpha 1-proteinase inhibitor by cleavage in the reactive site region. J Biol Chem. 1986 Nov 5;261(31):14748–14751. [PubMed] [Google Scholar]
  22. Johnson D. A., Travis J. Human alpha-1-proteinase inhibitor mechanism of action: evidence for activation by limited proteolysis. Biochem Biophys Res Commun. 1976 Sep 7;72(1):33–39. doi: 10.1016/0006-291x(76)90956-6. [DOI] [PubMed] [Google Scholar]
  23. Johnson D., Travis J. Structural evidence for methionine at the reactive site of human alpha-1-proteinase inhibitor. J Biol Chem. 1978 Oct 25;253(20):7142–7144. [PubMed] [Google Scholar]
  24. Kettner C. A., Shenvi A. B. Inhibition of the serine proteases leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin by peptide boronic acids. J Biol Chem. 1984 Dec 25;259(24):15106–15114. [PubMed] [Google Scholar]
  25. Kidd V. J., Wallace R. B., Itakura K., Woo S. L. alpha 1-antitrypsin deficiency detection by direct analysis of the mutation in the gene. Nature. 1983 Jul 21;304(5923):230–234. doi: 10.1038/304230a0. [DOI] [PubMed] [Google Scholar]
  26. Larsson C., Dirksen H., Sundström G., Eriksson S. Lung function studies in asymptomatic individuals with moderately (Pi SZ) and severely (Pi Z) reduced levels of alpha1-antitrypsin. Scand J Respir Dis. 1976;57(6):267–280. [PubMed] [Google Scholar]
  27. Morii M., Odani S., Ikenaka T. Characterization of a peptide released during the reaction of human alpha 1-antitrypsin and bovine alpha-chymotrypsin. J Biochem. 1979 Oct;86(4):915–921. doi: 10.1093/oxfordjournals.jbchem.a132623. [DOI] [PubMed] [Google Scholar]
  28. Mornex J. F., Chytil-Weir A., Martinet Y., Courtney M., LeCocq J. P., Crystal R. G. Expression of the alpha-1-antitrypsin gene in mononuclear phagocytes of normal and alpha-1-antitrypsin-deficient individuals. J Clin Invest. 1986 Jun;77(6):1952–1961. doi: 10.1172/JCI112524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mutharia L. M., Crockford G., Bogard W. C., Jr, Hancock R. E. Monoclonal antibodies specific for Escherichia coli J5 lipopolysaccharide: cross-reaction with other gram-negative bacterial species. Infect Immun. 1984 Sep;45(3):631–636. doi: 10.1128/iai.45.3.631-636.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nukiwa T., Satoh K., Brantly M. L., Ogushi F., Fells G. A., Courtney M., Crystal R. G. Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene. J Biol Chem. 1986 Dec 5;261(34):15989–15994. [PubMed] [Google Scholar]
  31. Owen M. C., Carrell R. W. alpha-1-Antitrypsin: sequence of the Z variant tryptic peptide. FEBS Lett. 1977 Jul 15;79(2):245–247. doi: 10.1016/0014-5793(77)80796-5. [DOI] [PubMed] [Google Scholar]
  32. Perlmutter D. H., Cole F. S., Goldberger G., Colten H. R. Distinct primary translation products from human liver mRNA give rise to secreted and cell-associated forms of complement protein C2. J Biol Chem. 1984 Aug 25;259(16):10380–10385. [PubMed] [Google Scholar]
  33. 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]
  34. Perlmutter D. H., Colten H. R., Grossberger D., Strominger J., Seidman J. G., Chaplin D. D. Expression of complement proteins C2 and factor B in transfected L cells. J Clin Invest. 1985 Oct;76(4):1449–1454. doi: 10.1172/JCI112123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Perlmutter D. H., Dinarello C. A., Punsal P. I., Colten H. R. Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest. 1986 Nov;78(5):1349–1354. doi: 10.1172/JCI112721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Perlmutter D. H., Goldberger G., Dinarello C. A., Mizel S. B., Colten H. R. Regulation of class III major histocompatibility complex gene products by interleukin-1. Science. 1986 May 16;232(4752):850–852. doi: 10.1126/science.3010455. [DOI] [PubMed] [Google Scholar]
  37. Perlmutter D. H., Kay R. M., Cole F. S., Rossing T. H., Van Thiel D., Colten H. R. The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA. Proc Natl Acad Sci U S A. 1985 Oct;82(20):6918–6921. doi: 10.1073/pnas.82.20.6918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Ritchie D. G., Levy B. A., Adams M. A., Fuller G. M. Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway. Proc Natl Acad Sci U S A. 1982 Mar;79(5):1530–1534. doi: 10.1073/pnas.79.5.1530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Roberts B. E., Paterson B. M. Efficient translation of tobacco mosaic virus RNA and rabbit globin 9S RNA in a cell-free system from commercial wheat germ. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2330–2334. doi: 10.1073/pnas.70.8.2330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rogers J., Kalsheker N., Wallis S., Speer A., Coutelle C. H., Woods D., Humphries S. E. The isolation of a clone for human alpha 1-antitrypsin and the detection of alpha 1-antitrypsin in mRNA from liver and leukocytes. Biochem Biophys Res Commun. 1983 Oct 31;116(2):375–382. doi: 10.1016/0006-291x(83)90532-6. [DOI] [PubMed] [Google Scholar]
  42. Sveger T. Prospective study of children with alpha 1-antitrypsin deficiency: eight-year-old follow-up. J Pediatr. 1984 Jan;104(1):91–94. doi: 10.1016/s0022-3476(84)80599-5. [DOI] [PubMed] [Google Scholar]
  43. Takemura S., Rossing T. H., Perlmutter D. H. A lymphokine regulates expression of alpha-1-proteinase inhibitor in human monocytes and macrophages. J Clin Invest. 1986 Apr;77(4):1207–1213. doi: 10.1172/JCI112423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Travis J., Bowen J., Baugh R. Human alpha-1-antichymotrypsin: interaction with chymotrypsin-like proteinases. Biochemistry. 1978 Dec 26;17(26):5651–5656. doi: 10.1021/bi00619a011. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. 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]
  48. Verbanac K. M., Heath E. C. Biosynthesis, processing, and secretion of M and Z variant human alpha 1-antitrypsin. J Biol Chem. 1986 Jul 25;261(21):9979–9989. [PubMed] [Google Scholar]
  49. 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]
  50. 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]
  51. Wigler M., Silverstein S., Lee L. S., Pellicer A., Cheng Y. c., Axel R. Transfer of purified herpes virus thymidine kinase gene to cultured mouse cells. Cell. 1977 May;11(1):223–232. doi: 10.1016/0092-8674(77)90333-6. [DOI] [PubMed] [Google Scholar]
  52. Yoshida A., Lieberman J., Gaidulis L., Ewing C. Molecular abnormality of human alpha1-antitrypsin variant (Pi-ZZ) associated with plasma activity deficiency. Proc Natl Acad Sci U S A. 1976 Apr;73(4):1324–1328. doi: 10.1073/pnas.73.4.1324. [DOI] [PMC free article] [PubMed] [Google Scholar]

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