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

FEBS Letters

Bugno, Marcin²  Bereta, Michal²  Witek, Barbara²  Bereta, Joanna²  Edwards, Dylan R.¹  Kordula, Tomasz² 

[1] School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK;Institute of Molecular Biology, Jagiellonian University, Al. Mickiewicza 3, 31-120 Cracow, Poland

关键词: Endothelial cell;    Astrocyte;    Inflammation;    Tissue inhibitor of metalloproteinases;    ECM;    extracellular matrix;    EtBr;    ethidium bromide;    FCS;    fetal calf serum;    iNOS;    inducible nitric oxide synthase;    OSM;    oncostatin M;    MBE;    murine brain microvascular endothelial cells;    MMP;    matrix metalloproteinases;    MS;    multiple sclerosis;    MT-MMP;    membrane-type MMP;    Stat;    signal transducer and activator of transcription;    TIMP;    tissue inhibitor of metalloproteinases;   

DOI  :  10.1016/S0014-5793(99)00323-3

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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-1β (IL-1β) and tumor necrosis factor-α (TNFα) exhibiting the strongest synergistic stimulation. Simultaneously, IL-1β/TNFα 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 TNFα or IFN-γ, whereas oncostatin M as well as TNFα 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.

【 授权许可】

Unknown