PREFERENTIAL INACTIVATION OF TISSUE INHIBITOR OF METALLOPROTEINASES-1 THAT IS BOUND TO THE PRECURSOR OF MATRIX METALLOPROTEINASE-9 (PROGELATINASE-B) BY HUMAN NEUTROPHIL ELASTASE

The precursor of matrix metalloproteinase 9 (pro-MMP-9) forms a complex with the tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule, and the N-terminal domain of TIMP-1 in the complex interacts and inhibits active MMPs. We have reported that a catalytic amount of MMP-3 (stromelysin 1) activates pro-MMP-9 (Ogata, Y., Enghild, J. J., and Nagase, H. (1992) J. Biol. Chem. 267, 3581-3584). To activate pro-MMP-9 in the complex, however, an excess molar amount of MMP-3 is required to saturate the TIMP-1 in the complex. The aim of this study was to test the hypothesis that the requirement for excess MMP-3 can be circumvented by specific destruction of TIMP-1 by non-target proteinases. We have tested trypsin, plasmin, cathepsin G, neutrophil elastase, and chymotrypsin as possible inactivators of TIMP-1 and found that neutrophil elastase inactivates TIMP-1 in the complex without significant destruction of pro-MMP-9. Once TIMP-1 is inactivated, pro MMP-9 can be readily activated by a catalytic amount of MMP-3. These results suggest that neutrophil elastase may participate in connective tissue destruction at the inflammatory sites not only by its direct action on matrix macromolecules but also by rendering pro-MMP-9 in the pro-MMP-9 . TIMP-1 complex activable by MMP-3 as well as activating pro MMP-3.