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

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Abstract
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.