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Published ahead of print on March 27, 2003, doi:10.1165/rcmb.2003-0034OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 283-294, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2003-0034OC

Inducible Expression of Tissue Inhibitor of Metalloproteinases–Resistant Matrix Metalloproteinase-9 on the Cell Surface of Neutrophils

Caroline A. Owen, Zhuma Hu, Brooke Barrick and Steven D. Shapiro

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah

Address correspondence to: Caroline A. Owen, M.D., Ph.D., Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 8th Floor Thorn Building, 75 Francis Street, Boston, MA 02115. E-mail: cowen{at}rics.bwh.harvard.edu

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 {alpha}1-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.

Abbreviations: 4-aminophenylmercuric acetate, APMA • N-formyl-leucyl-methionyl-phenylalanine, fMLP • interleukin, IL • lipopolysaccharide, LPS • 7-Methoxycoumarin-4-yl)-Acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L2,3-diaminopropionyl)-Ala-Arg-NH2, McaPLGLDpaAR • matrix metalloproteinase(s), MMP • membrane-type MMP(s), MT-MMP • neutrophil gelatinase B-associated lipocalin, NGAL • platelet-activating factor (1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine), PAF • polymorphonuclear neutrophils, PMN • tissue inhibitor of metalloproteinases, TIMP • tumor necrosis factor-{alpha}, TNF-{alpha}




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