Document Type

Article

Publication Date

5-1-2007

Keywords

Animals, Cathepsin B, Genes, Dominant, Humans, Interleukin-1 Receptor-Associated Kinases, Interleukin-8, Leukocyte Elastase, Lung, Macrophages, Matrix Metalloproteinase 2, Mice, Mice, Knockout, NF-kappa B, Pseudomonas Infections, Pseudomonas aeruginosa, Toll-Like Receptor 4, Transfection

Comments

This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org

Abstract

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-kappaB in macrophages, and inhibition of NF-kappaB 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.

Disciplines

Medicine and Health Sciences

Citation

Geraghty P, Rogan MP, Greene CM, Boxio RM, Poiriert T, O'Mahony M, Belaaouaj A, O'Neill SJ, Taggart CC, McElvaney NG. Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression. Journal of Immunology 2007 178(9):5871-8.

PubMed ID

17442971