Resistance of MMP9 and TIMP1 to endotoxin tolerance

Manoj Muthukuru, Christopher W. Cutler

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Inflammatory cytokines activate tissue collagenases such as matrix metalloproteinases (MMPs). MMPs are antagonized by tissue inhibitors of metalloproteinases (TIMPs) that attempt to regulate excessive collagenase activity during inflammatory conditions. During chronic inflammatory conditions, induction of endotoxin tolerance negatively regulates the cytokine response in an attempt to curtail excessive host tissue damage. However, little is known about how downregulation of inflammatory cytokines during endotoxin tolerance regulates MMP activities. In this study, human monocyte-derived macrophages were either sensitized or further challenged to induce tolerance with lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) or Escherichia coli (EcLPS). Inflammatory cytokines, such as TNFα and IL-1β, and levels of MMP9 and TIMP1 were analyzed by a combination of cytometric bead array, western blot/gelatin zymography and real-time RT-PCR. Functional blocking with anti-TLR4 but not with anti-TLR2 significantly downregulated TNFα and IL-1β. However, MMP9 levels were not inhibited by toll-like receptor (TLR) blocking. Interestingly, endotoxin tolerance significantly upregulated TIMP1 relative to MMP9 and downmodulated MMP9 secretion and its enzymatic activity. These results suggest that regulatory mechanisms such as induction of endotoxin tolerance could inhibit MMP activities and could facilitate restoring host tissue homeostasis.

Original languageEnglish (US)
JournalPathogens and Disease
Issue number5
StatePublished - Jul 1 2015


  • Endotoxin tolerance
  • Lipopolysaccharide
  • MMP
  • Macrophages
  • TIMP
  • Toll like receptors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology and Microbiology(all)
  • Microbiology (medical)
  • Infectious Diseases


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