10779/rcsi.10785809.v1
Patrick Geraghty
Patrick
Geraghty
Mark P. Rogan
Mark P.
Rogan
Catherine M. Greene
Catherine M.
Greene
Rachel MM Boxio
Rachel MM
Boxio
Tiphaine Poiriert
Tiphaine
Poiriert
Michael O'Mahony
Michael
O'Mahony
Abderazzaq Belaaouaj
Abderazzaq
Belaaouaj
Shane J. O'Neill
Shane J.
O'Neill
Clifford C. Taggart
Clifford C.
Taggart
Noel G. McElvaney
Noel G.
McElvaney
Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression.
Royal College of Surgeons in Ireland
2019
Animals
Cathepsin B
Genes
Dominant
Humans
Interleukin-1 Receptor-Associated Kinases
Interleukin-8
Leukocyte Elastase
Lung
Macrophages
Matrix Metalloproteinase 2
Mice
Knockout
NF-kappa B
Pseudomonas Infections
Pseudomonas aeruginosa
Toll-Like Receptor 4
Transfection
Medicine
2019-11-22 16:36:30
Journal contribution
https://repository.rcsi.com/articles/journal_contribution/Neutrophil_elastase_up-regulates_cathepsin_B_and_matrix_metalloprotease-2_expression_/10785809
<p>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.</p>