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首页> 外文期刊>Cellular Physiology and Biochemistry >Effect of proinflammatory cytokines, tumor necrosis factor-alpha and interferon-gamma on epithelial barrier function and matrix metalloproteinase-9 in Madin Darby canine kidney cells
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Effect of proinflammatory cytokines, tumor necrosis factor-alpha and interferon-gamma on epithelial barrier function and matrix metalloproteinase-9 in Madin Darby canine kidney cells

机译：促炎细胞因子，肿瘤坏死因子-α和干扰素-γ对Madin Darby犬肾细胞上皮屏障功能和基质金属蛋白酶9的影响

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Background: Elevated matrix metalloproteinase-9 production during inflammation may be deleterious to epithelial barrier function. Therefore we examined the effect of proinflammatory cytokines on the expression and regulation of matrix metalloproteinase-9 in a model renal epithelial cell system. Tight junctions limit diffusion between compartments and permit directional transport of solutes. Impairment of these junctional complexes by proteolysis may contribute to renal failure through loss of barrier function. Methods: The renal epithelial cell model, MDCK cells were employed to examine metalloproteinase activity and mRNA expression. Epithelial barrier function was determined using paracellular flux studies. Results: We found that matrix metalloproteinase-9 expression (MMP-9) and activity is markedly elevated in response to tumor necrosis factor-alpha exposure through a mitogen-activated protein kinase dependent pathway. The MMP-9 is predominately secreted into the apical compartment and elevated MMP-9 expression correlates with impaired cell barrier function that was restored using a specific inhibitor of MMP activity. Addition of recombinant MMP-9 to the apical compartment of MDCK cultures significantly elevated paracellular flux rate. Conclusions: We provide direct evidence for a MMP-9-mediated mechanism that produces junctional disruption. Collectively, these findings support the hypothesis that impaired epithelial barrier function due to activation of tissue/matrix degrading mechanisms occurs in response to specific inflammatory cues. Copyright (c) 2007 S. Karger AG, Basel.
机译：背景：炎症过程中基质金属蛋白酶9的产生升高可能对上皮屏障功能有害。因此，我们在模型肾上皮细胞系统中检查了促炎细胞因子对基质金属蛋白酶9表达和调控的影响。紧密的连接限制了隔室之间的扩散，并允许溶质定向输送。蛋白水解作用破坏这些连接复合物可能会导致屏障功能丧失，从而导致肾功能衰竭。方法：采用肾上皮细胞模型，MDCK细胞检测金属蛋白酶活性和mRNA表达。使用细胞旁通量研究确定上皮屏障功能。结果：我们发现基质金属蛋白酶9表达（MMP-9）和活性通过有丝分裂原激活的蛋白激酶依赖性途径对肿瘤坏死因子-α暴露有明显提高。 MMP-9主要分泌到根尖区，并且MMP-9表达升高与细胞屏障功能受损有关，后者通过使用MMP活性的特异性抑制剂得以恢复。将重组MMP-9添加到MDCK培养物的根部腔室中可显着提高细胞旁通量率。结论：我们提供了MMP-9介导的产生连接破坏的机制的直接证据。总的来说，这些发现支持以下假设：由于组织/基质降解机制的激活而导致的上皮屏障功能受损，是对特定炎症信号的反应。版权所有（c）2007 S.Karger AG，巴塞尔。

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