Inducible expression of tissue inhibitor of metalloproteinases–resistant matrix metalloproteinase-9 on the cell surface of neutrophils

CA Owen, Z Hu, B Barrick… - American journal of …, 2003 - atsjournals.org
CA Owen, Z Hu, B Barrick, SD Shapiro
American journal of respiratory cell and molecular biology, 2003atsjournals.org
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 …
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 (∼ 50%) and gelatin (∼ 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 α1-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 ∼ 21-fold and ∼ 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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