The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-α-induced expression of monocyte-chemoattractant protein-1 in endothelial cells
The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-α-induced expression of monocyte-chemoattractant protein-1 in endothelial cells
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DOI：
10.1182/blood.v93.3.857.403k03_857_865
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发表时间：
1999-02-01
期刊：
影响因子：
20.3
通讯作者：
Ludwig, S
中科院分区：
文献类型：
--
作者：
Goebeler, M;Kilian, K;Ludwig, S
单核细胞趋化蛋白-1 (MCP-1) 是趋化因子 C-C 亚家族的成员，对于将白细胞局部募集到炎症攻击部位非常重要。在这里，我们研究了涉及丝裂原激活蛋白 (MAP) 激酶超家族成员的内皮信号通路，并研究了它们在内皮中 MCP-1 表达的作用。我们发现肿瘤坏死因子-α (TNF-α) 是一种有效的内皮炎症激活剂，可导致人脐静脉内皮细胞 (HUVEC) 中 MAP 激酶 ERK、p38 和 JNK 的激活。然后使用流式细胞术、Northern印迹和荧光素酶报告基因测定通过药理学抑制和显性失活或组成型活性激酶突变体的瞬时表达来研究MAP激酶途径对TNF-α诱导的内皮MCP-1合成的贡献。抑制 Raf/MEK/ERK 或 SEK/JNK 通路对 MCP-1 水平没有显着影响，而通过 p38 抑制剂 SB203580 或 SB202190 或通过 p38 上游激活剂 MKK6 的显性失活突变体阻断 MKK6/p38 通路，可强烈抑制 TNF-α 诱导的 MCP-1 表达。与该发现一致，野生型或组成型活性 MKK6 的表达显着增强了限制 TNF-α 浓度对 MCP-1 合成的影响。这些数据表明 MKK6/p38 应激激酶级联在 TNF-α 介导的内皮 MCP-1 表达中发挥着至关重要的作用。 (C) 1999 年，美国血液学会。
Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C subfamily of chemokines, is important for the local recruitment of leukocytes to sites of inflammatory challenge. Here, we investigated endothelial signaling pathways involving members of the mitogen-activated protein (MAP) kinase superfamily and studied their role for MCP-1 expression in endothelium. We show that tumor necrosis factor-alpha (TNF-alpha), a potent inflammatory activator of endothelium, leads to activation of MAP kinases ERK, p38, and JNK in human umbilical vein endothelial cells (HUVEC). Contribution of MAP kinase pathways to TNF-alpha-induced synthesis of endothelial MCP-1 was then studied by pharmacologic inhibition and transient expression of dominant negative or constitutively active kinase mutants using flow cytometry, Northern blot, and luciferase reporter gene assays. Inhibition of Raf/MEK/ERK or SEK/JNK pathways had no significant effect on MCP-1 levels, whereas blocking the MKK6/p38 pathway by p38 inhibitors SB203580 or SB202190 or by a dominant negative mutant of MKK6, the upstream activator of p38, strongly inhibited TNF-alpha-induced expression of MCP-1. Consistent with that finding, expression of wild-type or constitutively active MKK6 significantly enhanced the effect of limiting TNF-alpha concentrations on MCP-1 synthesis. These data suggest a crucial role for the MKK6/p38 stress kinase cascade in TNF-alpha-mediated endothelial MCP-1 expression. (C) 1999 by The American Society of Hematology.