Tumor necrosis factor alpha stimulates cathepsin K and V activity via juxtacrine monocyte-endothelial cell signaling and JNK activation.
Tumor necrosis factor alpha stimulates cathepsin K and V activity via juxtacrine monocyte-endothelial cell signaling and JNK activation.
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DOI：
10.1007/s11010-012-1320-0
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发表时间：
2012-08
影响因子：
4.3
通讯作者：
Platt, Manu O.
中科院分区：
文献类型：
--
作者：
Keegan, Philip M.;Wilder, Catera L.;Platt, Manu O.
炎症和损伤促进单核细胞粘附到内皮和心血管疾病（CVD）。升高的炎症和增加的单核细胞-内皮细胞相互作用代表与多种心血管疾病相关的血管重塑的初始阶段。组织蛋白酶是由降解动脉壁中的弹性蛋白和胶原的两种细胞类型产生的蛋白酶，并且在心血管疾病中上调。我们假设炎性细胞因子肿瘤坏死因子α（TNFα）和单核细胞结合会刺激内皮细胞中组织蛋白酶K和V的表达和活性，这可能是心血管疾病期间启动局部蛋白水解的原因。用TNFα或THP-1单核细胞共培养物刺激汇合的人主动脉内皮细胞（HAECs），并使用多重组织蛋白酶酶谱法检测活性组织蛋白酶K、L、S和V水平的变化。与单独的任一细胞类型相比，用TNFα刺激的直接单核细胞-内皮细胞共培养物产生最大观察到的组织蛋白酶K和V活性（n=3，p<0.05）。用SP 6000125抑制JNK可阻断内皮细胞中组织蛋白酶K活性上调49%和组织蛋白酶V活性上调81%。总之，这些数据表明，炎症线索和单核细胞-内皮细胞相互作用通过JNK信号传导轴上调组织蛋白酶活性，并确定了一种新的机制，以减缓心血管疾病组织重塑的最早阶段。
Inflammation and damage promote monocyte adhesion to endothelium and cardiovascular disease (CVD). Elevated inflammation and increased monocyte-endothelial cell interactions represent the initial stages of vascular remodeling associated with a multitude of cardiovascular diseases. Cathepsins are proteases produced by both cell types that degrade elastin and collagen in arterial walls, and are upregulated in cardiovascular disease. We hypothesized that the inflammatory cytokine tumor necrosis factor alpha (TNFα) and monocyte binding would stimulate cathepsins K and V expression and activity in endothelial cells, that may be responsible for initiating local proteolysis during cardiovascular disease. Confluent human aortic endothelial cells (HAECs) were stimulated with TNFα or THP-1 monocyte co-cultures, and multiplex cathepsin zymography was used to detect changes in levels of active cathepsins K, L, S, and V. Direct monocyte-endothelial cell co-cultures stimulated with TNFα generated maximally observed cathepsin K and V activities compared to either cell type alone (n=3, p<0.05) by a c-Jun N-terminal kinase (JNK) dependent manner. Inhibition of JNK with SP6000125 blocked upregulation of cathepsin K activity by 49% and cathepsin V by 81% in endothelial cells. Together, these data show that inflammatory cues and monocyte-endothelial cell interactions upregulate cathepsin activity via JNK signaling axis and identify a new mechanism to target towards slowing the earliest stages of tissue remodeling in cardiovascular disease.
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影响因子：
4.8
作者：
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通讯作者：
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发表时间：
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影响因子：
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作者：
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