Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis.

Hdl Handle:
http://hdl.handle.net/10147/136779
Title:
Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis.
Authors:
Guyot, Nicolas; Butler, Marcus W; McNally, Paul; Weldon, Sinead; Greene, Catherine M; Levine, Rodney L; O'Neill, Shane J; Taggart, Clifford C; McElvaney, Noel G
Affiliation:
Pulmonary Research Division, Department of Medicine, The Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
Citation:
Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis. 2008, 283 (47):32377-85 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
21-Nov-2008
URI:
http://hdl.handle.net/10147/136779
DOI:
10.1074/jbc.M803707200
PubMed ID:
18799464
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed/18799464
Abstract:
Elafin is a neutrophil serine protease inhibitor expressed in lung and displaying anti-inflammatory and anti-bacterial properties. Previous studies demonstrated that some innate host defense molecules of the cystic fibrosis (CF) and chronic obstructive pulmonary disease airways are impaired due to increased proteolytic degradation observed during lung inflammation. In light of these findings, we thus focused on the status of elafin in CF lung. We showed in the present study that elafin is cleaved in sputum from individuals with CF. Pseudomonas aeruginosa-positive CF sputum, which was found to contain lower elafin levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective in cleaving recombinant elafin. NE plays a pivotal role in the process as only NE inhibitors are able to inhibit elafin degradation. Further in vitro studies demonstrated that incubation of recombinant elafin with excess of NE leads to the rapid cleavage of the inhibitor. Two cleavage sites were identified at the N-terminal extremity of elafin (Val-5-Lys-6 and Val-9-Ser-10). Interestingly, purified fragments of the inhibitor (Lys-6-Gln-57 and Ser-10-Gln-57) were shown to still be active for inhibiting NE. However, NE in excess was shown to strongly diminish the ability of elafin to bind lipopolysaccharide (LPS) and its capacity to be immobilized by transglutamination. In conclusion, this study provides evidence that elafin is cleaved by its cognate enzyme NE present at excessive concentration in CF sputum and that P. aeruginosa infection promotes this effect. Such cleavage may have repercussions on the innate immune function of elafin.
Item Type:
Article
Language:
en
MeSH:
Cross-Linking Reagents; Cystic Fibrosis; Dose-Response Relationship, Drug; Elafin; Fibronectins; Humans; Leukocyte Elastase; Lipopolysaccharides; Models, Biological; Protein Binding; Protein Structure, Tertiary; Pseudomonas Infections; Pseudomonas aeruginosa; Recombinant Proteins; Sputum
ISSN:
0021-9258

Full metadata record

DC FieldValue Language
dc.contributor.authorGuyot, Nicolasen
dc.contributor.authorButler, Marcus Wen
dc.contributor.authorMcNally, Paulen
dc.contributor.authorWeldon, Sineaden
dc.contributor.authorGreene, Catherine Men
dc.contributor.authorLevine, Rodney Len
dc.contributor.authorO'Neill, Shane Jen
dc.contributor.authorTaggart, Clifford Cen
dc.contributor.authorMcElvaney, Noel Gen
dc.date.accessioned2011-07-25T08:34:28Z-
dc.date.available2011-07-25T08:34:28Z-
dc.date.issued2008-11-21-
dc.identifier.citationElafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis. 2008, 283 (47):32377-85 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid18799464-
dc.identifier.doi10.1074/jbc.M803707200-
dc.identifier.urihttp://hdl.handle.net/10147/136779-
dc.description.abstractElafin is a neutrophil serine protease inhibitor expressed in lung and displaying anti-inflammatory and anti-bacterial properties. Previous studies demonstrated that some innate host defense molecules of the cystic fibrosis (CF) and chronic obstructive pulmonary disease airways are impaired due to increased proteolytic degradation observed during lung inflammation. In light of these findings, we thus focused on the status of elafin in CF lung. We showed in the present study that elafin is cleaved in sputum from individuals with CF. Pseudomonas aeruginosa-positive CF sputum, which was found to contain lower elafin levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective in cleaving recombinant elafin. NE plays a pivotal role in the process as only NE inhibitors are able to inhibit elafin degradation. Further in vitro studies demonstrated that incubation of recombinant elafin with excess of NE leads to the rapid cleavage of the inhibitor. Two cleavage sites were identified at the N-terminal extremity of elafin (Val-5-Lys-6 and Val-9-Ser-10). Interestingly, purified fragments of the inhibitor (Lys-6-Gln-57 and Ser-10-Gln-57) were shown to still be active for inhibiting NE. However, NE in excess was shown to strongly diminish the ability of elafin to bind lipopolysaccharide (LPS) and its capacity to be immobilized by transglutamination. In conclusion, this study provides evidence that elafin is cleaved by its cognate enzyme NE present at excessive concentration in CF sputum and that P. aeruginosa infection promotes this effect. Such cleavage may have repercussions on the innate immune function of elafin.-
dc.language.isoenen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/18799464en
dc.subject.meshCross-Linking Reagents-
dc.subject.meshCystic Fibrosis-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshElafin-
dc.subject.meshFibronectins-
dc.subject.meshHumans-
dc.subject.meshLeukocyte Elastase-
dc.subject.meshLipopolysaccharides-
dc.subject.meshModels, Biological-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Structure, Tertiary-
dc.subject.meshPseudomonas Infections-
dc.subject.meshPseudomonas aeruginosa-
dc.subject.meshRecombinant Proteins-
dc.subject.meshSputum-
dc.titleElafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis.en
dc.typeArticleen
dc.contributor.departmentPulmonary Research Division, Department of Medicine, The Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.en
dc.identifier.journalThe Journal of biological chemistryen
dc.description.provinceLeinster-

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