Pulmonary proteases in the cystic fibrosis lung induce interleukin 8 expression from bronchial epithelial cells via a heme/meprin/epidermal growth factor receptor/Toll-like receptor pathway.

Hdl Handle:
http://hdl.handle.net/10147/207190
Title:
Pulmonary proteases in the cystic fibrosis lung induce interleukin 8 expression from bronchial epithelial cells via a heme/meprin/epidermal growth factor receptor/Toll-like receptor pathway.
Authors:
Cosgrove, Sonya; Chotirmall, Sanjay H; Greene, Catherine M; McElvaney, Noel G
Affiliation:
Respiratory Research Division, Department of Medicine, Royal College of Surgeons , in Ireland, Beaumont Hospital, Dublin 9, Ireland.
Citation:
J Biol Chem. 2011 Mar 4;286(9):7692-704. Epub 2010 Dec 30.
Journal:
The Journal of biological chemistry
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207190
DOI:
10.1074/jbc.M110.183863
PubMed ID:
21193404
Abstract:
A high intrapulmonary protease burden is characteristic of cystic fibrosis (CF), and the resulting dysregulation of the protease/anti-protease balance has serious implications for inflammation in the CF lung. Because of this inflammation, micro-bleeds can occur releasing hemoglobin into the lung. The aim of this study was to investigate the effect of the protease-rich environment of the CF lung on human hemoglobin and to assess the proinflammatory effect of heme on CF bronchial epithelium. Here, we show that the Pseudomonas proteases (Pseudomonas elastase and alkaline protease) and the neutrophil proteases (neutrophil elastase (NE) and proteinase-3) are capable of almost complete degradation of hemoglobin in vitro but that NE is the predominant protease that cleaves hemoglobin in vivo in CF bronchoalveolar lavage fluid. One of the effects of this is the release of heme, and in this study we show that heme stimulates IL-8 and IL-10 protein production from DeltaF508 CFBE41o(-) bronchial epithelial cells. In addition, heme-induced IL-8 expression utilizes a novel pathway involving meprin, EGF receptor, and MyD88. Meprin levels are elevated in CF cell lines and bronchial brushings, thus adding to the proinflammatory milieu. Interestingly, alpha(1)-antitrypsin, in addition to its ability to neutralize NE and protease-3, can also bind heme and neutralize heme-induced IL-8 from CFBE41o(-) cells. This study illustrates the proinflammatory effects of micro-bleeds in the CF lung, the process by which this occurs, and a potential therapeutic intervention.
Language:
eng
MeSH:
Bronchoalveolar Lavage Fluid/cytology; Cell Line; Cystic Fibrosis/immunology/*metabolism/microbiology; Epithelial Cells/metabolism/pathology; Heme/*metabolism; Hemoglobins/metabolism; Humans; Interleukin-10/metabolism; Interleukin-8/*metabolism; Leukocyte Elastase/*metabolism; Metalloendopeptidases/genetics/metabolism; Myeloblastin/*metabolism; Peptide Hydrolases/metabolism; Pneumonia, Bacterial/immunology/metabolism; Pseudomonas Infections/immunology/metabolism; Pseudomonas aeruginosa/enzymology; Receptor, Epidermal Growth Factor/metabolism; Respiratory Mucosa/metabolism/pathology; Serine Endopeptidases/metabolism; Signal Transduction/*physiology; Toll-Like Receptors/metabolism
ISSN:
1083-351X (Electronic); 0021-9258 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorCosgrove, Sonyaen_GB
dc.contributor.authorChotirmall, Sanjay Hen_GB
dc.contributor.authorGreene, Catherine Men_GB
dc.contributor.authorMcElvaney, Noel Gen_GB
dc.date.accessioned2012-02-01T10:01:31Z-
dc.date.available2012-02-01T10:01:31Z-
dc.date.issued2012-02-01T10:01:31Z-
dc.identifier.citationJ Biol Chem. 2011 Mar 4;286(9):7692-704. Epub 2010 Dec 30.en_GB
dc.identifier.issn1083-351X (Electronic)en_GB
dc.identifier.issn0021-9258 (Linking)en_GB
dc.identifier.pmid21193404en_GB
dc.identifier.doi10.1074/jbc.M110.183863en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207190-
dc.description.abstractA high intrapulmonary protease burden is characteristic of cystic fibrosis (CF), and the resulting dysregulation of the protease/anti-protease balance has serious implications for inflammation in the CF lung. Because of this inflammation, micro-bleeds can occur releasing hemoglobin into the lung. The aim of this study was to investigate the effect of the protease-rich environment of the CF lung on human hemoglobin and to assess the proinflammatory effect of heme on CF bronchial epithelium. Here, we show that the Pseudomonas proteases (Pseudomonas elastase and alkaline protease) and the neutrophil proteases (neutrophil elastase (NE) and proteinase-3) are capable of almost complete degradation of hemoglobin in vitro but that NE is the predominant protease that cleaves hemoglobin in vivo in CF bronchoalveolar lavage fluid. One of the effects of this is the release of heme, and in this study we show that heme stimulates IL-8 and IL-10 protein production from DeltaF508 CFBE41o(-) bronchial epithelial cells. In addition, heme-induced IL-8 expression utilizes a novel pathway involving meprin, EGF receptor, and MyD88. Meprin levels are elevated in CF cell lines and bronchial brushings, thus adding to the proinflammatory milieu. Interestingly, alpha(1)-antitrypsin, in addition to its ability to neutralize NE and protease-3, can also bind heme and neutralize heme-induced IL-8 from CFBE41o(-) cells. This study illustrates the proinflammatory effects of micro-bleeds in the CF lung, the process by which this occurs, and a potential therapeutic intervention.en_GB
dc.language.isoengen_GB
dc.subject.meshBronchoalveolar Lavage Fluid/cytologyen_GB
dc.subject.meshCell Lineen_GB
dc.subject.meshCystic Fibrosis/immunology/*metabolism/microbiologyen_GB
dc.subject.meshEpithelial Cells/metabolism/pathologyen_GB
dc.subject.meshHeme/*metabolismen_GB
dc.subject.meshHemoglobins/metabolismen_GB
dc.subject.meshHumansen_GB
dc.subject.meshInterleukin-10/metabolismen_GB
dc.subject.meshInterleukin-8/*metabolismen_GB
dc.subject.meshLeukocyte Elastase/*metabolismen_GB
dc.subject.meshMetalloendopeptidases/genetics/metabolismen_GB
dc.subject.meshMyeloblastin/*metabolismen_GB
dc.subject.meshPeptide Hydrolases/metabolismen_GB
dc.subject.meshPneumonia, Bacterial/immunology/metabolismen_GB
dc.subject.meshPseudomonas Infections/immunology/metabolismen_GB
dc.subject.meshPseudomonas aeruginosa/enzymologyen_GB
dc.subject.meshReceptor, Epidermal Growth Factor/metabolismen_GB
dc.subject.meshRespiratory Mucosa/metabolism/pathologyen_GB
dc.subject.meshSerine Endopeptidases/metabolismen_GB
dc.subject.meshSignal Transduction/*physiologyen_GB
dc.subject.meshToll-Like Receptors/metabolismen_GB
dc.titlePulmonary proteases in the cystic fibrosis lung induce interleukin 8 expression from bronchial epithelial cells via a heme/meprin/epidermal growth factor receptor/Toll-like receptor pathway.en_GB
dc.contributor.departmentRespiratory Research Division, Department of Medicine, Royal College of Surgeons , in Ireland, Beaumont Hospital, Dublin 9, Ireland.en_GB
dc.identifier.journalThe Journal of biological chemistryen_GB
dc.description.provinceLeinster-

Related articles on PubMed

All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.