Type

Other / n/a

Authors

Noel G McElvaney
Shane J O'Neill
Clifford C Taggart
Abderazzaq Belaaouaj
Patrick Geraghty
Cliona Kenna
Erwin E Sterchi
Catherine M Greene
David A Bergin

Subjects

Biochemistry

Topics
epithelial cells nf kappa b interleukin 8 myeloid differentiation factor 88 receptor epidermal growth factor bronchi transforming growth factor alpha cell line enzyme activation medicine and health sciences rna messenger thiopronine rna messenger bronchoalveolar lavage fluid humans gene expression regulation metalloproteases leukocyte elastase receptor epidermal growth factor

Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. (2008)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> Medicine Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Medicine

Full list of authors on original publication

Noel G McElvaney, Shane J O'Neill, Clifford C Taggart, Abderazzaq Belaaouaj, Patrick Geraghty, Cliona Kenna, Erwin E Sterchi, Catherine M Greene, David A Bergin

Experts in our system

1
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
 
2
Shane J O'Neill
Royal College of Surgeons in Ireland
Total Publications: 84
 
3
Clifford C Taggart
Royal College of Surgeons in Ireland
Total Publications: 54
 
4
Patrick Geraghty
Royal College of Surgeons in Ireland
Total Publications: 13
 
5
Catherine M Greene
Royal College of Surgeons in Ireland
Total Publications: 150
 
6
David A Bergin
Royal College of Surgeons in Ireland
Total Publications: 28