Tumor necrosis factor-α disruption of brain endothelial cell barrier is mediated through matrix metalloproteinase-9

Am J Surg. 2014 Dec;208(6):954-60; discussion 960. doi: 10.1016/j.amjsurg.2014.08.014. Epub 2014 Sep 28.

Abstract

Traumatic brain injuries cause vascular hyperpermeability. Tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), and caspase-3 may be important in these processes but the relationship between them has not been investigated. We hypothesized that TNF-α regulates caspase-3-mediated hyperpermeability and blood brain barrier damage and hyperpermeability directly or indirectly via activation of MMP-9. To test this, rat brain microvascular endothelial cells were treated with TNF-α with or without inhibition of MMP-9. Monolayer permeability was measured, zonula occludens-1 and F-actin configuration were examined, and MMP-9 and caspase-3 activities were quantified. TNF-α increased monolayer permeability, damaged zonula occludens-1, induced filamentous-actin stress fiber formation, and increased both MMP-9 and caspase-3 activities. Inhibition of MMP-9 attenuated these changes. These data highlight a novel link between TNF-α and MMP-9 and show that TNF-α regulated caspase-3-mediated hyperpermeability and vascular damage may be linked to MMP-9 in vitro. These findings augment the understanding of traumatic brain injury and pave the way for improved treatment.

Keywords: Blood brain barrier; Caspase-3; Gelatinase B; Matrix metalloproteinase; Traumatic brain injury; Tumor necrosis factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Brain / cytology*
  • Brain Injuries / metabolism
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Rats
  • Tumor Necrosis Factor-alpha / metabolism*
  • Zonula Occludens-1 Protein / metabolism

Substances

  • Matrix Metalloproteinase Inhibitors
  • TJP1 protein, human
  • Tumor Necrosis Factor-alpha
  • Zonula Occludens-1 Protein
  • Caspase 3
  • Matrix Metalloproteinase 9