Reprogramming of TIMP#x2010;1 and TIMP#x2010;3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines

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-1beta; (IL-1beta;) and tumor necrosis factor-alpha; (TNFalpha;) exhibiting the strongest synergistic stimulation. Simultaneously, IL-1beta;/TNFalpha; almost completely blocks TIMP-3 expression. Both synergistic effects are dose-dependent within the concentration range 0.05ndash;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 TNFalpha; or IFN-gamma;, whereas oncostatin M as well as TNFalpha; 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.