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.
Affiliation
Respiratory Research Division, Department of Medicine, Royal College of Surgeons , in Ireland, Beaumont Hospital, Dublin 9, Ireland.Issue Date
2012-02-01T10:01:31ZMeSH
Bronchoalveolar Lavage Fluid/cytologyCell 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
Metadata
Show full item recordCitation
J Biol Chem. 2011 Mar 4;286(9):7692-704. Epub 2010 Dec 30.Journal
The Journal of biological chemistryDOI
10.1074/jbc.M110.183863PubMed ID
21193404Abstract
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
engISSN
1083-351X (Electronic)0021-9258 (Linking)
ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M110.183863