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J. Biol. Chem., Vol. 283, Issue 46, 31736-31744, November 14, 2008

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Activation of the Epidermal Growth Factor Receptor (EGFR) by a Novel Metalloprotease Pathway^*

David A. Bergin¹, Catherine M. Greene¹², Erwin E. Sterchi, Cliona Kenna, Patrick Geraghty, Abderazzaq Belaaouaj^¶, Clifford C. Taggart³, Shane J. O'Neill, and Noel G. McElvaney

From the Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland, the Institute of Biochemistry and Molecular Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland, and ^¶INSERM UMR514, IFR 53, Hospital Maison Blanche, CHU de Reimis, France

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 TGF 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. NFB 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.

Received for publication, May 15, 2008 , and in revised form, August 8, 2008.

^* This work was supported by The Alpha One Foundation, The Medical Research Charities Group/Health Research Board, The Children's Research Centre, Crumlin Hospital, and The Swiss National Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to the study.

³ Current address: School of Medicine and Dentistry, Queen's University, Belfast, UK. E-mail: c.taggart{at}qub.ac.uk.

² To whom correspondence should be addressed: Respiratory Research Division, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. Tel.: 00353-1-809-3800; Fax: 00353-1-809-3808; E-mail: cmgreene{at}rcsi.ie.

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