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

• Published in: Microbiology and immunology Vol. 54; no. 7; p. 417
• Main Authors: Tsuge, Mitsuru, Yasui, Kozo, Ichiyawa, Takashi, Saito, Yukie, Nagaoka, Yoshiharu, Yashiro, Masato, Yamashita, Nobuko, Morishima, Tsuneo
• Format: Journal Article
• Language: English
• Published: Australia 01.07.2010
• Subjects: Animals; Blood-Brain Barrier - enzymology; Brain - enzymology; Enzyme Activation; Male; Matrix Metalloproteinase 9 - blood; Matrix Metalloproteinase 9 - cerebrospinal fluid; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Inbred C57BL; Tumor Necrosis Factor-alpha - blood
• ISSN: 0385-5600
• DOI: 10.1111/j.1348-0421.2010.00226.x

Increases of cytokine in the blood play important roles in the pathogenesis of influenza-associated encephalopathy. TNF-alpha 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-alpha 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-alpha in the blood, such as sepsis, burns, trauma and influenza-associated encephalopathy.