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

Bergin, David A; Greene, Catherine M; Sterchi, Erwin E; Kenna, Cliona; Geraghty, Patrick; Belaaouaj, Abderazzaq; Taggart, Clifford C; O'Neill, Shane J; McElvaney, Noel G (2008). Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. Journal of biological chemistry, 283(46), pp. 31736-44. Bethesda, Md.: American Society for Biochemistry and Molecular Biology 10.1074/jbc.M803732200

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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:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
UniBE Contributor:	Sterchi, Erwin-Ernst
ISSN:	0021-9258
ISBN:	18772136
Publisher:	American Society for Biochemistry and Molecular Biology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:03
Last Modified:	05 Dec 2022 14:19
Publisher DOI:	10.1074/jbc.M803732200
PubMed ID:	18772136
Web of Science ID:	000260760800056
URI:	https://boris.unibe.ch/id/eprint/27325 (FactScience: 106041)