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

Cytokine-dependent regulation of tissue inhibitors of metalloproteinases (T IMPs) expression provides an important mechanism for controlling the activi ty of matrix metalloproteinases. We present data indicating that during inf lammatory processes TIMP-1 and TIMP-3 may be involved in the proteolytic re modeling of subendothelial basement membrane of the brain microvascular sys tem, a key step during leukocyte migration into the brain perivascular tiss ue. In brain endothelial cells the expression of TMP-1 is dramatically up-r egulated by major proinflammatory cytokines, with the combination of interl eukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) exhibi ting the strongest synergistic stimulation. Simultaneously, IL-1 beta/TNF a lpha almost completely blocks TIMP-3 expression. Both synergistic effects a re dose-dependent within the concentration range 0.05-5 ng/ml of both cytok ines 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 TNF alpha or IFN-gamma, wherea s oncostatin M as well as TNF alpha up-regulate TIMP-1 mRNA level. We propo se 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, (C) 1999 Federation of European Biochemical Societies.