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Activation of macrophage promatrix metalloproteinase-9 by lipopolysaccharide-associated proteinases
Danqing Min1, Anthony G Moore, Michael A Bain
1Kanematsu Laboratories, Sydney Cancer Center, Royal Prince Alfred Hospital, University of Sydney, Missenden Road, Camperdown, Sydney, New South Wales 2050, Australia.
Abstract:
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.
Insights
Lipopolysaccharide (LPS) activates proMMP9 in macrophages via associated proteinases, promoting extracellular matrix degradation. This activation doesn't influence proMMP9 gene expression, highlighting distinct regulatory pathways.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Lipopolysaccharide (LPS) is known to up-regulate promatrix metalloproteinase-9 (proMMP9) gene expression in monocytes/macrophages.
- Matrix metalloproteinases (MMPs) play a critical role in extracellular matrix (ECM) remodeling and degradation.
Purpose of the Study:
- To investigate the mechanism by which LPS activates proMMP9 in human macrophages.
- To determine the role of LPS-associated proteinases in proMMP9 activation and gene expression.
Main Methods:
- Activation of proMMP9 in human macrophages and THP-1 cells using LPS preparations.
- Characterization of LPS-associated proteinases, including their substrate specificity (gelatin, alpha(1)-proteinase inhibitor).
- Assessment of the effect of inhibiting LPS-associated proteinases on proMMP9 synthesis and activation.
Main Results:
- LPS preparations activate proMMP9 in human macrophages and THP-1 cells via associated serine proteinases.
- These proteinases cleave the proMMP9 N-terminal propeptide, similar to organomercurial compound activation.
- LPS-associated proteinases degrade gelatin and alpha(1)-proteinase inhibitor, favoring ECM degradation.
- A low molecular mass inhibitor of MMP9 is generated during proMMP9 activation.
- Inhibition of LPS-associated proteinases did not affect proMMP9 gene expression, decoupling activation from synthesis signaling.
Conclusions:
- LPS activates pre-existing proMMP9 through associated serine proteinases, independent of de novo gene synthesis signaling.
- This activation contributes to ECM degradation by cleaving MMP9 and its inhibitors.
- The findings reveal a dual role for LPS in modulating MMP9 activity and ECM turnover.
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