Activation of macrophage promatrix metalloproteinase-9 by lipopolysaccharide-associated proteinases.
LPS induces an up-regulation of promatrix metalloproteinase-9 (proMMP9) gene expression in cells of the monocyte/macrophage lineage. We demonstrate here that LPS preparations are also able to activate proMMP9 made by human macrophages or THP-1 cells via LPS-associated proteinases, which cleave the N-terminal propeptide at a site or sites close to the one cleaved upon activation with organomercurial compounds. LPS-associated proteinases are serine proteinases that are able to cleave denatured collagens (gelatin) and the mammalian serine proteinase inhibitor, alpha(1)-proteinase inhibitor, thereby pushing the balance of extracellular matrix turnover even further toward degradation. A low molecular mass, low affinity inhibitor of MMP9, possibly derived from the propeptide, is generated during proMMP9 activation. However, inhibition of the LPS-associated proteinases had no effect on proMMP9 synthesis, indicating that their proteolytic activity was not required for signaling the up-regulation of the proMMP9 gene.
Min
Danqing
D
Kanematsu Laboratories, Sydney Cancer Center, Royal Prince Alfred Hospital, University of Sydney, Missenden Road, Camperdown, Sydney, New South Wales 2050, Australia.
Moore
Anthony G
AG
Bain
Michael A
MA
Breit
Samuel N
SN
Lyons
J Guy
JG
D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D012697:Serine Endopeptidases / Q000502:physiology*
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D012697:Serine Endopeptidases; D017364:Collagenases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9