Increase of tumor necrosis factor-α in the blood induces early activation of matrix metalloproteinase-9 in the brain

Mitsuru Tsuge, Kozo Yasui, Takashi Ichiyawa, Yukie Saito, Yoshiharu Nagaoka, Masato Yashiro, Nobuko Yamashita, Tsuneo Morishima

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


Increases of cytokine in the blood play important roles in the pathogenesis of influenza-associated encephalopathy. TNF-α was administered intravenously to wild-type mice, after which blood, CSF and brain tissue were obtained, and changes in BBB permeability, the amounts of MMP-9 and TIMP-1, and the localization of activated MMP were assessed. There was a significant increase in BBB permeability after 6 and 12 hr. MMP-9 was increased after 3 hr in the brain and cerebrospinal fluid, which was earlier than in the serum. TIMP-1 protein in the brain increased significantly after MMP-9 had increased. Activation of MMP-9 was observed in neurons in the cerebral cortex and hippocampus, and in vascular endothelial cells. These findings suggest that an increase in blood TNF-α promotes activation of MMP-9 in the brain, and may also induce an increase in permeability of the BBB. Early activation of MMP-9 in the brain may contribute to an early onset of neurological disorders and brain edema prior to multiple organ failure in those inflammatory diseases associated with highly increased concentrations of TNF-α in the blood, such as sepsis, burns, trauma and influenza-associated encephalopathy,

Original languageEnglish
Pages (from-to)417-424
Number of pages8
Issue number7
Publication statusPublished - Jul 2010


  • Blood-brain barrier
  • Influenza associated encephalopathy
  • Matrix metalloproteinase-9
  • Tumor necrosis factor-alpha

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology


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