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Respiratory Research
Published in: Respiratory Research 1/2008

Open Access 01-12-2008 | Research

Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI) by lung epithelial cells: role of charge of the proteinase-inhibitor complex

Authors: Anita L Sullivan, Timothy Dafforn, Pieter S Hiemstra, Robert A Stockley

Published in: Respiratory Research | Issue 1/2008

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Abstract

Background

Secretory leukoproteinase inhibitor (SLPI) is an important inhibitor of neutrophil elastase (NE), a proteinase implicated in the pathogenesis of lung diseases such as COPD. SLPI also has antimicrobial and anti-inflammatory properties, but the concentration of SLPI in lung secretions in COPD varies inversely with infection and the concentration of NE. A fall in SLPI concentration is also seen in culture supernatants of respiratory cells exposed to NE, for unknown reasons. We investigated the hypothesis that SLPI complexed with NE associates with cell membranes in vitro.

Methods

Respiratory epithelial cells were cultured in the presence of SLPI, varying doses of proteinases over time, and in different experimental conditions. The likely predicted charge of the complex between SLPI and proteinases was assessed by theoretical molecular modelling.

Results

We observed a rapid, linear decrease in SLPI concentration in culture supernatants with increasing concentration of NE and cathepsin G, but not with other serine proteinases. The effect of NE was inhibited fully by a synthetic NE inhibitor only when added at the same time as NE. Direct contact between NE and SLPI was required for a fall in SLPI concentration. Passive binding to cell culture plate materials was able to remove a substantial amount of SLPI both with and without NE. Theoretical molecular modelling of the structure of SLPI in complex with various proteinases showed a greater positive charge for the complex with NE and cathepsin G than for other proteinases, such as trypsin and mast cell tryptase, that also bind SLPI but without reducing its concentration.

Conclusion

These data suggest that NE-mediated decrease in SLPI is a passive, charge-dependent phenomenon in vitro, which may correlate with changes observed in vivo.
Literature
1.
Thompson RC, Ohlsson K: Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci U S A 1986, 83:6692–6696.CrossRefPubMedPubMedCentral
2.
Smith CE, Johnson DA: Human bronchial leucocyte proteinase inhibitor. Rapid isolation and kinetic analysis with human leucocyte proteinases. Biochem J 1985,225(2):463–472.CrossRefPubMedPubMedCentral
3.
Ohlsson K, Tegner H, Akesson U: Isolation and partial characterization of a low molecular weight acid stable protease inhibitor from human bronchial secretion. Hoppe Seylers Z Physiol Chem 1977,358(5):583–589.CrossRefPubMed
4.
Hiemstra PS, Maassen RJ, Stolk J, Heinzel-Wieland R, Steffens GJ, Dijkman JH: Antibacterial activity of antileukoprotease. Infect Immun 1996,64(11):4520–4524.PubMedPubMedCentral
5.
Singh PK, Tack BF, McCray PB Jr., Welsh MJ: Synergistic and additive killing by antimicrobial factors found in human airway surface liquid. Am J Physiol Lung Cell Mol Physiol 2000,279(5):L799-L805.PubMed
6.
Fahey JV, Wira CR: Effect of menstrual status on antibacterial activity and secretory leukocyte protease inhibitor production by human uterine epithelial cells in culture. J Infect Dis 2002, 185:1606–1613.CrossRefPubMed
7.
Tomee JF, Hiemstra PS, Heinzel-Wieland R, Kauffman HF: Antileukoprotease: an endogenous protein in the innate mucosal defense against fungi. J Infect Dis 1997,176(3):740–747.CrossRefPubMed
8.
Hocini H, Becquart P, Bouhlal H, Adle-Biassette H, Kazatchkine MD, Belec L: Secretory leukocyte protease inhibitor inhibits infection of monocytes and lymphocytes with human immunodeficiency virus type 1 but does not interfere with transcytosis of cell-associated virus across tight epithelial barriers. Clin Diagn Lab Immunol 2000, 7:515–518.PubMedPubMedCentral
9.
Beppu Y, Imamura Y, Tashiro M, Towatari T, Ariga H, Kido H: Human mucus protease inhibitor in airway fluids is a potential defensive compound against infection with influenza A and Sendai viruses. J Biochem 1997,121(2):309–316.CrossRefPubMed
10.
Taggart CC, Greene CM, McElvaney MG, O'Neill S: Secretory leucoprotease inhibitor prevents LPS-induced IkB alpha degradation without affecting phosphorylation or ubiquitination. J Biol Chem 2002, 277:33648–33653.CrossRefPubMed
11.
Ding A, Thieblemont N, Zhu J, Jin F, Zhang J, Wright S: Secretory leukocyte protease inhibitor interferes with uptake of lipopolysaccharide by macrophages. Infect Immun 1999,67(9):4485–4489.PubMedPubMedCentral
12.
Taggart CC, Cryan SA, Weldon S, Gibbons A, Greene CM, Kelly E, Low TB, O'Neill SJ, McElvaney NG: Secretory leucoprotease inhibitor binds to NF-kB binding sites in monocytes and inhibits p65 binding. J Exp Med 2005, 202:1659–1668.CrossRefPubMedPubMedCentral
13.
Greene CM, McElvaney NG, O'Neill SJ, Taggart CC: Secretory leucoprotease inhibitor impairs toll-like receptor 2- and 4-mediated responses in monocytic cells. Infect Immun 2004, 72:3684–3687.CrossRefPubMedPubMedCentral
14.
Song X, Zeng L, Jin W, Thompson J, Mizel DE, Lei K, Billinghurst RC, Poole AR, Wahl SM: Secretory leukocyte protease inhibitor suppresses the inflammation and joint damage of bacterial cell wall-induced arthritis. J Exp Med 1999, 190:535–542.CrossRefPubMedPubMedCentral
15.
Stockley RA, Morrison HM: Elastase inhibitors of the respiratory tract. Eur Respir J 1990, 3 Suppl 9:9s-15s.
16.
Hill AT, Campbell EJ, Bayley DL, Hill SL, Stockley RA: Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). Am J Respir Crit Care Med 1999,160(6):1968–1975.CrossRefPubMed
17.
Dijkman JH, Kramps JA, Franken C: Antileukoprotease in sputum during bronchial infections. Chest 1986, 89:731–736.CrossRefPubMed
18.
White AJ, Gompertz S, Bayley DL, Hill SL, O'Brien C, Unsal I, Stockley RA: Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis. Thorax 2003, 58:680–685.CrossRefPubMedPubMedCentral
19.
Gompertz S, Bayley DL, Hill SL, Stockley RA: Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD. Thorax 2001, 56:36–41.CrossRefPubMedPubMedCentral
20.
Hill AT, Bayley D, Stockley RA: The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med 1999, 160:893–898.CrossRefPubMed
21.
Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA: Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000, 109:288–295.CrossRefPubMed
22.
Draper DL, Landers DV, Krohn MA, Hillier SL, Wiesenfeld HC, Heine RP: Levels of vaginal secretory leukocyte protease inhibitor are decreased in women with lower reproductive tract infections. Am J Obstet Gynecol 2000, 183:1243–1248.CrossRefPubMed
23.
Piccioni PD, Kramps JA, Rudolphus A, Bulgheroni A, Luisetti M: Proteinase/proteinase inhibitor imbalance in sputum sol phases from patients with chronic obstructive pulmonary disease. Suggestions for a key role played by antileukoprotease. Chest 1992, 102:1470–1476.CrossRefPubMed
24.
Abe T, Kobayashi N, Yoshimura K, Trapnell BC, Kim H, Hubbard RC, Brewer MT, Thompson RC, Crystal RG: Expression of the secretory leukoprotease inhibitor gene in epithelial cells. J Clin Invest 1991, 87:2207–2215.CrossRefPubMedPubMedCentral
25.
Saitoh H, Masuda T, Shimura S, Fushimi T, Shirato K: Secretion and gene expression of secretory leukocyte protease inhibitor by human airway submucosal glands. Am J Physiol Lung Cell Mol Physiol 2001,280(1):L79-L87.PubMed
26.
Sallenave JM, Shulmann J, Crossley J, Jordana M, Gauldie J: Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. Am J Respir Cell Mol Biol 1994,11(6):733–741.CrossRefPubMed
27.
van Wetering S, van der Linden AC, van Sterkenburg MA, Rabe KF, Schalkwijk J, Hiemstra PS: Regulation of secretory leukocyte proteinase inhibitor (SLPI) production by human bronchial epithelial cells: increase of cell- associated SLPI by neutrophil elastase. J Investig Med 2000,48(5):359–366.PubMed
28.
Marchand V, Tournier JM, Polette M, Nawrocki B, Fuchey C, Pierrot D, Burlet H, Puchelle E: The elastase-induced expression of secretory leukocyte protease inhibitor is decreased in remodelled airway epithelium. Eur J Pharmacol 1997, 336:187–196.CrossRefPubMed
29.
Abbinante-Nissen JM, Simpson LG, Leikauf GD: Neutrophil elastase increases secretory leukocyte protease inhibitor transcript levels in airway epithelial cells. Am J Physiol 1993,265(3 Pt 1):L286-L292.PubMed
30.
Owen CA, Campbell MA, Boukedes SS, Campbell EJ: Cytokines regulate membrane-bound leukocyte elastase on neutrophils: a novel mechanism for effector activity. Am J Physiol Lung Cell Mol Physiol 1997, 272:L385-L393.
31.
Owen CA, Campbell MA, Sannes PL, Boukedes SS, Campbell EJ: Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases. J Cell Biol 1995, 131:775–789.CrossRefPubMed
32.
Navia MA, McKeever BM, Springer JP, Lin TY, Williams HR, Fluder EM, Dorn CP, Hoogsteen K: Structure of human neutrophil elastase in complex with a peptide chloromethyl ketone inhibitor at 1.84-Å resolution. Proc Natl Acad Sci USA 1989, 86:7–11.CrossRefPubMedPubMedCentral
33.
Grütter MG, Fendrich G, Huber R, Bode W: The 2.5 A X-ray crystal structure of the acid-stable proteinase inhibitor from human mucous secretions analysed in its complex with bovine alpha-chymotrypsin. EMBO J 1988,7(2):345–351.PubMedPubMedCentral
34.
Ma G, Greenwell-Wild T, Lei K, Jin W, Swisher J, Hardegen N, Wild CT, Wahl SM: Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection. J Exp Med 2004, 200:1337–1346.CrossRefPubMedPubMedCentral
35.
Tseng CC, Tseng CP: Identification of a novel secretory leukocyte protease inhibitor-binding protein involved in membrane phospholipid movement. FEBS Lett 2000, 475:232–236.CrossRefPubMed
36.
Perlmutter DH, Glover GI, Rivetna M, Schasteen CS, Fallon RJ: Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes. Proc Natl Acad Sci USA 1990, 87:3753–3757.CrossRefPubMedPubMedCentral
37.
Sallenave JM, M. ST, Cox G, Chignard M, Gauldie J: Secretory leukocyte proteinase inhibitor is a major leukocyte elastase inhibitor in human neutrophils. J Leukoc Biol 1997, 61:695–702.PubMed
38.
Schulze H, Korpal M, Bergmeier W, Italiano JE, Wahl SM, Shivdasani RA: Interactions between the megakaryocyte/platelet-specific b1 tubulin and the secretory leukocyte protease inhibitor SLPI suggest a role for regulated proteolysis in platelet functions. Blood 2004, 104:3949–3957.CrossRefPubMed
39.
Martodam RR, Baugh RJ, Twumasi DY, Liener IE: A rapid procedure for the large scale purification of elastase from human sputum. Preparative Biochemistry 1979, 9:15–31.CrossRefPubMed
40.
Veale CA, Bernstein PR, Bohnert CM, Brown FJ, Bryant C, Damewood JR, Earley R, Feeney SW, Edwards PD, Gomes B, Hulsizer JM, Kosmider BJ, Krell RD, Moore G, Salcedo TW, Shaw A, Silberstein DS, Steelman GB, Stein M, Strimpler A, Thomas RM, Vacek EP, Williams JC, Wolanin DJ, Woolson S: Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase. J Med Chem 1997, 40:3173–3181.CrossRefPubMed
41.
Dupuit F, Jacquot J, Spilmont C, Tournier JM, Hinnrasky J, Puchelle E: Vectorial delivery of newly-synthesized secretory proteins by human tracheal gland cells in culture. Epithelial Cell Biol 1993,2(3):91–99.PubMed
42.
Macdonald SJ, Dowle MD, Harrison LA, Clarke GD, Inglis GG, Johnson MR, Shah P, Smith RA, Amour A, Fleetwood G, Humphreys DC, Molloy CR, Dixon M, Godward RE, Wonacott AJ, Singh OM, Hodgson ST, Hardy GW: Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW475151). J Med Chem 2002, 45:3878–3890.CrossRefPubMed
43.
de Garavilla L, Greco MN, Sukumar N, Chen ZW, Pineda AO, Mathews FS, Di Cera E, Giardino EC, Wells GI, Haertlein BJ, Kauffman JA, Corcoran TW, Derian CK, Eckardt AJ, Damiano BP, Andrade-Gordon P, Maryanoff BE: A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo. J Biol Chem 2005, 280:18001–18007.CrossRefPubMed
44.
Park EY, Kim JA, Kim HW, Kim YS, Song HK: Crystal structure of the Bowman-Birk inhibitor from barley seeds in ternary complex with porcine trypsin. J Mol Biol 2004, 343:173–186.CrossRefPubMed
45.
Levell J, Astles P, Eastwood P, Cairns J, Houille O, Aldous S, Merriman G, Whiteley B, Pribish J, Czekaj M, Liang G, Maignan S, Guilloteau JP, Dupuy A, Davidson J, Harrison T, Morley A, Watson S, Fenton G, McCarthy C, Romano J, Mathew R, Engers D, Gardyan M, Sides K, Kwong J, Tsay J, Rebello S, Shen L, Wang J, Luo Y, Giardino O, Lim HK, Smith K, Pauls H: Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase. Bioorg Med Chem 2005, 13:2859–2872.CrossRefPubMed
46.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Research 2000, 28:235–242.CrossRefPubMedPubMedCentral
47.
Guex N, Peitsch MC: SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 1997, 18:2714–2723.CrossRefPubMed
48.
Llewellyn-Jones CG, Lomas DA, Stockley RA: Potential role of recombinant secretory leucoprotease inhibitor in the prevention of neutrophil mediated matrix degradation. Thorax 1994,49(6):567–572.CrossRefPubMedPubMedCentral
49.
Kramps JA, Te Boekhorst AH, Fransen JA, Ginsel LA, Dijkman JH: Antileukoprotease is associated with elastin fibers in the extracellular matrix of the human lung. An immunoelectron microscopic study. Am Rev Respir Dis 1989,140(2):471–476.CrossRefPubMed
50.
Van Seuningen I, Aubert JP, Davril M: Interaction between secretory leucoprotease inhibitor and bronchial mucins or glycopeptides. Physiopathological implications for the protection of mucins against proteolysis by human leucocyte elastase. Biochem J 1992,281(Pt 3):761–766.CrossRefPubMedPubMedCentral
51.
Miller KW, Evans RJ, Eisenberg SP, Thompson RC: Secretory leukocyte protease inhibitor binding to mRNA and DNA as a possible cause of toxicity to Escherichia coli. J Bacteriol 1989, 171:2166–2172.PubMedPubMedCentral
52.
Bruch M, Bieth JG: Influence of elastin on the inhibition of leucocyte elastase by a1-proteinase inhibitor and bronchial inhibitor. Biochem J 1986, 238:269–273.CrossRefPubMedPubMedCentral
Metadata
Title
Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI) by lung epithelial cells: role of charge of the proteinase-inhibitor complex
Authors
Anita L Sullivan
Timothy Dafforn
Pieter S Hiemstra
Robert A Stockley
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2008
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-9-60

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