title: Reprogramming of TIMP-1 and TIMP-3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines.
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-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) exhibiting the strongest synergistic stimulation. Simultaneously, IL-1beta/TNF alpha 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 TNF alpha or IFN-gamma whereas oncostatin M as well as TNF alpha 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.
authors.affiliation: Institute of Molecular Biology, Jagiellonian University, Cracow, Poland. marcinb@arches.uga.edu
authors.forename: M
authors.initials: M
authors.lastname: Bugno
authors.forename: B
authors.initials: B
authors.lastname: Witek
authors.forename: J
authors.initials: J
authors.lastname: Bereta
authors.forename: M
authors.initials: M
authors.lastname: Bereta
authors.forename: D R
authors.initials: DR
authors.lastname: Edwards
authors.forename: T
authors.initials: T
authors.lastname: Kordula
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000166:cytology / Q000201:enzymology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; C508351:OSM protein, human; D010455:Peptides; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D053683:Oncostatin M; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat