Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway.

Hdl Handle:
http://hdl.handle.net/10147/136789
Title:
Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway.
Authors:
Bergin, David A; Greene, Catherine M; Sterchi, Erwin E; Kenna, Cliona; Geraghty, Patrick; Belaaouaj, Abderrazzaq; Taggart, Clifford C; O'Neill, Shane J; McElvaney, Noel G
Affiliation:
Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
Citation:
Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. 2008, 283 (46):31736-44 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
14-Nov-2008
URI:
http://hdl.handle.net/10147/136789
DOI:
10.1074/jbc.M803732200
PubMed ID:
18772136
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed/18772136
Abstract:
Neutrophil Elastase (NE) is a pro-inflammatory protease present at higher than normal levels in the lung during inflammatory disease. NE regulates IL-8 production from airway epithelial cells and can activate both EGFR and TLR4. TACE/ADAM17 has been reported to trans-activate EGFR in response to NE. Here, using 16HBE14o-human bronchial epithelial cells we demonstrate a new mechanism by which NE regulates both of these events. A high molecular weight soluble metalloprotease activity detectable only in supernatants from NE-treated cells by gelatin and casein zymography was confirmed to be meprin alpha by Western immunoblotting. In vitro studies demonstrated the ability of NE to activate meprin alpha, which in turn could release soluble TGFalpha and induce IL-8 production from 16HBE14o- cells. These effects were abrogated by actinonin, a specific meprin inhibitor. NE-induced IL-8 expression was also inhibited by meprin alpha siRNA. Immunoprecipitation studies detected EGFR/TLR4 complexes in NE-stimulated cells overexpressing these receptors. Confocal studies confirmed colocalization of EGFR and TLR4 in 16HBE14o- cells stimulated with meprin alpha. NFkappaB was also activated via MyD88 in these cells by meprin alpha. In bronchoalveolar lavage fluid from NE knock-out mice infected intra-tracheally with Pseudomonas aeruginosa meprin alpha was significantly decreased compared with control mice, and was significantly increased and correlated with NE activity, in bronchoalveolar lavage fluid from individuals with cystic fibrosis but not healthy controls. The data describe a previously unidentified lung metalloprotease meprin alpha, and its role in NE-induced EGFR and TLR4 activation and IL-8 production.
Item Type:
Article
Language:
en
MeSH:
Bronchi; Bronchoalveolar Lavage Fluid; Cell Line; Enzyme Activation; Epithelial Cells; Gene Expression Regulation; Humans; Interleukin-8; Leukocyte Elastase; Metalloproteases; Myeloid Differentiation Factor 88; NF-kappa B; RNA, Messenger; Receptor, Epidermal Growth Factor; Tiopronin; Transforming Growth Factor alpha
ISSN:
0021-9258

Full metadata record

DC FieldValue Language
dc.contributor.authorBergin, David Aen
dc.contributor.authorGreene, Catherine Men
dc.contributor.authorSterchi, Erwin Een
dc.contributor.authorKenna, Clionaen
dc.contributor.authorGeraghty, Patricken
dc.contributor.authorBelaaouaj, Abderrazzaqen
dc.contributor.authorTaggart, Clifford Cen
dc.contributor.authorO'Neill, Shane Jen
dc.contributor.authorMcElvaney, Noel Gen
dc.date.accessioned2011-07-25T08:34:56Z-
dc.date.available2011-07-25T08:34:56Z-
dc.date.issued2008-11-14-
dc.identifier.citationActivation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. 2008, 283 (46):31736-44 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid18772136-
dc.identifier.doi10.1074/jbc.M803732200-
dc.identifier.urihttp://hdl.handle.net/10147/136789-
dc.description.abstractNeutrophil Elastase (NE) is a pro-inflammatory protease present at higher than normal levels in the lung during inflammatory disease. NE regulates IL-8 production from airway epithelial cells and can activate both EGFR and TLR4. TACE/ADAM17 has been reported to trans-activate EGFR in response to NE. Here, using 16HBE14o-human bronchial epithelial cells we demonstrate a new mechanism by which NE regulates both of these events. A high molecular weight soluble metalloprotease activity detectable only in supernatants from NE-treated cells by gelatin and casein zymography was confirmed to be meprin alpha by Western immunoblotting. In vitro studies demonstrated the ability of NE to activate meprin alpha, which in turn could release soluble TGFalpha and induce IL-8 production from 16HBE14o- cells. These effects were abrogated by actinonin, a specific meprin inhibitor. NE-induced IL-8 expression was also inhibited by meprin alpha siRNA. Immunoprecipitation studies detected EGFR/TLR4 complexes in NE-stimulated cells overexpressing these receptors. Confocal studies confirmed colocalization of EGFR and TLR4 in 16HBE14o- cells stimulated with meprin alpha. NFkappaB was also activated via MyD88 in these cells by meprin alpha. In bronchoalveolar lavage fluid from NE knock-out mice infected intra-tracheally with Pseudomonas aeruginosa meprin alpha was significantly decreased compared with control mice, and was significantly increased and correlated with NE activity, in bronchoalveolar lavage fluid from individuals with cystic fibrosis but not healthy controls. The data describe a previously unidentified lung metalloprotease meprin alpha, and its role in NE-induced EGFR and TLR4 activation and IL-8 production.-
dc.language.isoenen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/18772136en
dc.subject.meshBronchi-
dc.subject.meshBronchoalveolar Lavage Fluid-
dc.subject.meshCell Line-
dc.subject.meshEnzyme Activation-
dc.subject.meshEpithelial Cells-
dc.subject.meshGene Expression Regulation-
dc.subject.meshHumans-
dc.subject.meshInterleukin-8-
dc.subject.meshLeukocyte Elastase-
dc.subject.meshMetalloproteases-
dc.subject.meshMyeloid Differentiation Factor 88-
dc.subject.meshNF-kappa B-
dc.subject.meshRNA, Messenger-
dc.subject.meshReceptor, Epidermal Growth Factor-
dc.subject.meshTiopronin-
dc.subject.meshTransforming Growth Factor alpha-
dc.titleActivation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway.en
dc.typeArticleen
dc.contributor.departmentRespiratory Research Division, Department of Medicine, 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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