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dc.contributor.authorBergin, David A
dc.contributor.authorGreene, Catherine M
dc.contributor.authorSterchi, Erwin E
dc.contributor.authorKenna, Cliona
dc.contributor.authorGeraghty, Patrick
dc.contributor.authorBelaaouaj, Abderrazzaq
dc.contributor.authorTaggart, Clifford C
dc.contributor.authorO'Neill, Shane J
dc.contributor.authorMcElvaney, Noel G
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
html.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.


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