Reprogramming of TIMP-1 and TIMP-3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines

FEBS Lett. 1999 Apr 1;448(1):9-14. doi: 10.1016/s0014-5793(99)00323-3.


Cytokine-dependent regulation of tissue inhibitors of metalloproteinases (TIMPs) expression provides an important mechanism for controlling the activity of matrix metalloproteinases. We present data indicating that during inflammatory processes TIMP-1 and TIMP-3 may be involved in the proteolytic remodeling of subendothelial basement membrane of the brain microvascular system, a key step during leukocyte migration into the brain perivascular tissue. In brain endothelial cells the expression of TIMP-1 is dramatically up-regulated by major proinflammatory cytokines, with the combination of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) exhibiting the strongest synergistic stimulation. Simultaneously, IL-1beta/TNF alpha almost completely blocks TIMP-3 expression. Both synergistic effects are dose-dependent within the concentration range 0.05-5 ng/ml of both cytokines and correlate with the expression of inducible nitric oxide synthase, an endothelial cell activation marker. Down-regulation of TIMP-3 expression is also detected in astrocytes treated with TNF alpha or IFN-gamma whereas oncostatin M as well as TNF alpha up-regulate TIMP-1 mRNA level. We propose that the cytokine-modified balance between TIMP-1 and TIMP-3 expression provides a potential mechanism involved in the regulation of microvascular basement membrane proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / enzymology
  • Brain / cytology
  • Brain / enzymology
  • Cells, Cultured
  • Cytokines / metabolism*
  • Cytokines / pharmacology
  • Endothelium, Vascular / cytology
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Inflammation Mediators / pharmacology
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Oncostatin M
  • Peptides / pharmacology
  • Rats
  • Rats, Wistar
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*
  • Tissue Inhibitor of Metalloproteinase-3 / genetics*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / genetics


  • Cytokines
  • Inflammation Mediators
  • Interleukin-1
  • OSM protein, human
  • Peptides
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-3
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Oncostatin M
  • Interferon-gamma
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat