Reprogramming of TIMP-1 and TIMP-3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines
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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DOI：
10.1016/s0014-5793(99)00323-3
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发表时间：
1999-04-01
期刊：
影响因子：
3.5
通讯作者：
Kordula, T
中科院分区：
文献类型：
--
作者：
Bugno, M;Witek, B;Kordula, T
细胞因子依赖性调节组织金属蛋白酶抑制剂（TIMPs）的表达是调控基质金属蛋白酶活性的重要机制。我们提供的数据表明，在炎症过程中，TIMP-1和TIMP-3可能参与了脑微血管系统内皮下基底膜的蛋白水解重塑，这是白细胞迁移到脑血管周围组织的关键步骤。在脑内皮细胞中，主要的促炎细胞因子显著上调TMP-1的表达，其中白细胞介素-1 β (IL-1 β)和肿瘤坏死因子- α (TNF α)联合作用表现出最强的协同刺激。同时，IL-1 β /TNF α几乎完全阻断TIMP-3的表达。两种细胞因子在0.05-5 ng/ml浓度范围内的协同效应均呈剂量依赖性，并与诱导型一氧化氮合酶（内皮细胞活化标志物）的表达相关。在TNF α或ifn - γ处理的星形胶质细胞中，也检测到TIMP-3表达下调，而肿瘤抑制素M和TNF α上调TIMP-1 mRNA水平。我们提出，细胞因子修饰的TIMP-1和TIMP-3表达之间的平衡提供了一种参与微血管基底膜蛋白水解调节的潜在机制，(C) 1999年欧洲生化学会联合会。
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 TMP-1 is dramatically up-regulated by major proinflammatory cytokines, with the combination of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) exhibiting the strongest synergistic stimulation. Simultaneously, IL-1 beta/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, (C) 1999 Federation of European Biochemical Societies.