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Neutrophil Elastase Up-Regulates Cathepsin B and Matrix Metalloprotease-2 Expression¹

Patrick Geraghty^2,*, Mark P. Rogan^2,*, Catherine M. Greene^*, Rachel M. M. Boxio, Tiphaine Poiriert, Michael O’Mahony^*, Abderazzaq Belaaouaj, Shane J. O’Neill^*, Clifford C. Taggart^3,* and Noel G. McElvaney^*

^* Pulmonary Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland; and Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche Santé 514, Institut Fédératif de Recherche 53, Centre Hospitalier Universitaire Maison Blanche, Reims, France

Neutrophil elastase (NE) activity is increased in many diseases. Other families of proteases, including cathepsins and matrix metalloproteases (MMPs), are also present at elevated levels in similar disease conditions. We postulated that NE could induce expression of cathepsins and MMPs in human macrophages. NE exposure resulted in macrophages, producing significantly greater amounts of cathepsin B and latent and active MMP-2. Cathepsin B and MMP-2 activities were decreased in Pseudomonas-infected NE knockout mice compared with wild-type littermates. We also demonstrate that NE can activate NF-B in macrophages, and inhibition of NF-B resulted in a reduction of NE-induced cathepsin B and MMP-2. Also, inhibition of TLR-4 or transfection of macrophages with dominant-negative IL-1R-associated kinase-1 resulted in a reduction of NE-induced cathepsin B and MMP-2. This study describes for the first time a novel hierarchy among proteases whereby a serine protease up-regulates expression of MMPs and cathepsins. This has important implications for therapeutic intervention in protease-mediated diseases.

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 This work was supported by the Health Research Board, the Alpha One Foundation, the Program for Research in Third Levels Institutes administered by Higher Education Authority, Science Foundation Ireland, Cystic Fibrosis Hope Source, Cystic Fibrosis Research Trust, Cystic Fibrosis Association of Ireland, and the Royal College of Surgeons in Ireland.

² P.G. and M.P.R. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Clifford C. Taggart, Pulmonary Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. E-mail address: ctaggart{at}rcsi.ie

⁴ Abbreviations used in this paper: MMP, matrix metalloprotease; IRAK, IL-1R-associated kinase; MDM, monocyte-derived macrophage; NE, neutrophil elastase; PAR, protease-activated receptor.

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