Background: An imbalance between neutrophil protease and surrounding antiprotease levels has been shown to be important in the pathogenesis of chronic obstructive pulmonary disease (COPD). Adenoviral E1A DNA and protein are frequently detected in the lungs of COPD patients. As secretory leukoprotease inhibitor (SLPI) and elafin/skin-derived antileukoproteinase (SKALP) are locally produced in the lung and inhibit neutrophil elastase activity, we hypothesized that adenoviral E1A might affect the production of these antiproteases. Objectives: To examine the effect of E1A on SLPI and elafin/SKALP secretion in A549 (alveolar epithelial) cells and primary human bronchial epithelial (HBE) cells. Methods: SLPI and elafin/SKALP were quantitated from cell culture supernatants using an ELISA. SLPI mRNA expression was examined by Northern blotting, and SLPI promoter activity was measured using a reporter gene assay. Results: E1A significantly suppressed SLPI and elafin/SKALP secretion by A549 cells upon interleukin (IL)-1β stimulation. E1A also suppressed SLPI and elafin/SKALP secretion by HBE cells. SLPI mRNA expression in A549 cells was suppressed by E1A regardless of IL-1β stimulation. IL-1β-induced SLPI promoter activity was suppressed by E1A gene transfection into A549 cells. Conclusions: Our findings of adenoviral E1A-mediated suppression of SLPI and elafin/SKALP secretion suggest that E1A may be involved in the enhancement of alveolar damage and play a role in the COPD process.

Keywords:
A549 cells, Adenovirus E1A, Bronchial epithelial cells, Elafin/SKALP, Reporter gene assay, Secretory leukoprotease inhibitor
1.
Lenfant C, Khaltaev N: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report, 2003, updated.
2.
Hoshino Y, Nagai S, Koyama H, Okuda K, Nishimura K, Miki H, Hamada K, Izumi T: Airflow limitation in Japanese smokers: significance of serum neutrophil elastase/alpha1-proteinase inhibitor ratio and FEV1 (%pred) adjusted by pack-years. Respiration 2000;67:372–377.
3.
Cichy J, Potempa J, Travis J: Biosynthesis of α1-proteinase inhibitor by human lung-derived epithelial cells. J Biol Chem 1997;272:8250–8255.
4.
Hu C, Perlmutter DH: Cell-specific involvement of HNF-1β in α1-antitrypsin gene expression in human respiratory epithelial cells. Am J Physiol Lung Cell Mol Physiol 2002;282:L757–L765.
5.
Stetler G, Brewer MT, Thompson RC: Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases. Nucleic Acids Res 1986;14:7883–7896.
6.
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 USA 1986;83:6692–6696.
7.
Abe T, Kobayashi N, Yoshimura K, et al: Expression of the secretory leukoprotease inhibitor gene in epithelial cells. J Clin Invest 1991;87:2207–2215.
8.
Kikuchi T, Abe T, Satoh K, et al: Cis-acting region associated with lung cell-specific expression of the secretory leukoprotease inhibitor gene. Am J Respir Cell Mol Biol 1997;17:361–367.
9.
Hogg JC: Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2001;164:S71–S75.
10.
Vitalis TZ, Keicho N, Itabashi S, Hayashi S, Hogg JC: A model of latent adenovirus 5 infection in the guinea pig (Cavia porcellus). Am J Respir Cell Mol Biol 1996;14:225–231.
11.
McNeely TB, Dealy M, Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM: Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J Clin Invest 1995;96:456–464.
12.
Jin FY, Nathan C, Radzioch D, Ding A: Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 1997;88:417–426.
13.
Retamales I, Elliott WM, Meshi B, et al: Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001;164:469–473.
14.
Vitalis TZ, Kern I, Croome A, Behzad H, Hayashi S, Hogg JC: The effect of latent adenovirus 5 infection on cigarette smoke-induced lung inflammation. Eur Respir J 1998;11:664–669.
15.
Higashimoto Y, Keicho N, Elliott WM, Hogg JC, Hayashi S: Effect of adenovirus E1A on ICAM-1 promoter activity in human alveolar and bronchial epithelial cells. Gene Expr 1999;8:287–297.
16.
Keicho N, Elliott WM, Hogg JC, Hayashi S: Adenovirus E1A upregulates interleukin-8 expression induced by endotoxin in pulmonary epithelial cells. Am J Physiol 1997;272:L1046–L1052.
17.
Keicho N, Elliott WM, Hogg JC, Hayashi S: Adenovirus E1A gene dysregulates ICAM-1 expression in transformed pulmonary epithelial cells. Am J Respir Cell Mol Biol 1997;16:23–30.
18.
Higashimoto Y, Elliott WM, Behzad AR, et al: Inflammatory mediator mRNA expression by adenovirus E1A transfected bronchial epithelial cells. Am J Respir Crit Care Med 2002;166:200–207.
19.
Keicho N, Higashimoto Y, Bondy GP, Elliott WM, Hogg JC, Hayashi S: Endotoxin-specific NF-κB activation in pulmonary epithelial cells harboring adenovirus E1A. Am J Physiol 1999;277:L523–L532.
20.
Matsuse T, Hayashi S, Kuwano K, Keunecke H, Jefferies WA, Hogg JC: Latent adenoviral infection in the pathogenesis of chronic airways obstruction. Am Rev Respir Dis 1992;146:177–184.
21.
Elliott WM, Hayashi S, Hogg JC: Immunodetection of adenoviral E1A proteins in human lung tissue. Am J Respir Cell Mol Biol 1995;12:642–648.
22.
Carrell RW, Jeppsson JO, Laurell CB, et al: Structure and variation of human alpha 1-antitrypsin. Nature 1982;298:329–334.
23.
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.
24.
Snider GL, Lucey EC, Christensen TG, et al: Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products. Am Rev Respir Dis 1984;129:155–160.
25.
Amitani R, Wilson R, Rutman A, et al: Effects of human neutrophil elastase and Pseudomonas aeruginosa proteinases on human respiratory epithelium. Am J Respir Cell Mol Biol 1991;4:26–32.
26.
Smallman LA, Hill SL, Stockley RA: Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax 1984;39:663–667.
27.
Tosi MF, Zakem H, Berger M: Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J Clin Invest 1990;86:300–308.
28.
Hiemstra PS, Maassen RJ, Stolk J, Heinzel-Wieland R, Steffens GJ, Dijkman JH: Antibacterial activity of antileukoprotease. Infect Immun 1996;64:4520–4524.
29.
Tomee JF, Hiemstra PS, Heinzel-Wieland R, Kauffman HF: Antileukoprotease: an endogenous protein in the innate mucosal defense against fungi. J Infect Dis 1997;176:740–747.
30.
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.
31.
Betsuyaku T, Takeyabu K, Tanino M, Nishimura M: Role of secretory leukocyte protease inhibitor in the development of subclinical emphysema. Eur Respir J 2002;19:1051–1057.
32.
Jaumann F, Elssner A, Mazur G, Dobmann S, Vogelmeier C: Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line. Munich Lung Transplant Group. Eur Respir J 2000;15:1052–1057.
33.
Nguyen H, Teskey L, Lin R, Hiscott J: Identification of the secretory leukocyte protease inhibitor (SLPI) as a target of IRF-1 regulation. Oncogene 1999;18:5455–5463.
34.
Feigenblum D, Walker R, Schneider RJ: Adenovirus induction of an interferon-regulatory factor during entry into the late phase of infection. J Virol 1998;72:9257–9266.
35.
Schalkwijk J, Wiedow O, Hirose S: The trappin gene family: proteins defined by an N-terminal transglutaminase substrate domain and a C-terminal four-disulphide core. Biochem J 1999;340(Pt 3):569–577.
36.
Schalkwijk J, de Roo C, de Jongh GJ: Skin-derived antileukoproteinase (SKALP), an elastase inhibitor from human keratinocytes. Purification and biochemical properties. Biochim Biophys Acta 1991;1096:148–154.
37.
Birrer P: Proteases and antiproteases in cystic fibrosis: pathogenetic considerations and therapeutic strategies. Respiration 1995;62(suppl 1):25–28.
38.
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;11:733–741.
39.
Calikoglu M, Sahin G, Unlu A, Ozturk C, Tamer L, Ercan B, Kanik A, Atik U: Leptin and TNF-alpha levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional parameters. Respiration 2004;71:45–50.
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2005
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