title: Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression.
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.
authors: Pulmonary Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors: Patrick
authors: P
authors: Geraghty
authors: Mark P
authors: MP
authors: Rogan
authors: Catherine M
authors: CM
authors: Greene
authors: Rachel M M
authors: RM
authors: Boxio
authors: Tiphaine
authors: T
authors: Poiriert
authors: Michael
authors: M
authors: O'Mahony
authors: Abderazzaq
authors: A
authors: Belaaouaj
authors: Shane J
authors: SJ
authors: O'Neill
authors: Clifford C
authors: CC
authors: Taggart
authors: Noel G
authors: NG
authors: McElvaney
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019272:Leukocyte Elastase / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011552:Pseudomonas Infections / Q000276:immunology; D011550:Pseudomonas aeruginosa; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014162:Transfection
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D019272:Leukocyte Elastase; D002401:Cathepsin B; D020778:Matrix Metalloproteinase 2