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Inducible expression of tissue inhibitor of metalloproteinases-resistant matrix metalloproteinase-9 on the cell surface of neutrophils.
Owen, Caroline A; Hu, Zhuma; Barrick, Brooke; Shapiro, Steven D.
Affiliation
  • Owen CA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. cowen@rics.bwh.harvard.edu
Am J Respir Cell Mol Biol ; 29(3 Pt 1): 283-94, 2003 Sep.
Article in En | MEDLINE | ID: mdl-12663332
Matrix metalloproteinase (MMP)-9 secreted by activated polymorphonuclear neutrophils (PMN) may play roles in mediating lung injury by degrading extracellular matrix proteins. However, the mechanisms by which MMP-9 retains activity in the presence of tissue inhibitors of metalloproteinases (TIMPs) are not known. We show that MMP-9 is also expressed on the cell surface of PMN, and proinflammatory mediators induce up to 10-fold increases in cell surface expression of MMP-9. Stimulated human PMN express active forms of cell surface MMP, which cleave the MMP substrate, McaPLGLDpaAR. Loss-of-function studies employing PMN from mice genetically deficient in MMP-9 (MMP-9-/-) demonstrate that membrane-bound MMP-9 contributes substantially to MMP-mediated surface-bound cleavage of McaPLGLDpaAR (approximately 50%) and gelatin (approximately 70%) by stimulated PMN. Like soluble MMP-9, membrane-bound MMP-9 cleaves McaPLGLDpaAR (Kcat/KM = 82,000 M-1s-1), gelatin, type IV collagen, elastin, and alpha1-proteinase inhibitor. However, in contrast to soluble MMP-9, membrane-bound MMP-9 is substantially resistant to inhibition by TIMPs. The IC50 for inhibition of membrane-bound MMP-9 by TIMP-1 and TIMP-2 are approximately 21-fold and approximately 68-fold higher, respectively, than those for inhibition of soluble MMP-9. The binding of MMP-9 to the plasma membrane of PMN enables it to evade inhibition by TIMPs, and thereby may alter the pericellular proteolytic balance in favor of extracellular matrix degradation. Membrane-bound MMP-9 on PMN may play pathogenetic roles in inflammatory lung diseases.
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Database: MEDLINE Main subject: Cell Membrane / Tissue Inhibitor of Metalloproteinases / Matrix Metalloproteinase 9 / Neutrophils Limits: Animals / Humans Language: En Year: 2003 Type: Article
Search on Google
Database: MEDLINE Main subject: Cell Membrane / Tissue Inhibitor of Metalloproteinases / Matrix Metalloproteinase 9 / Neutrophils Limits: Animals / Humans Language: En Year: 2003 Type: Article