Inhibition of p38 mitogen-activated protein kinase ameliorates cytokine up-regulated shigatoxin-1 toxicity in human brain microvascular endothelial cells.
Inhibition of p38 mitogen-activated protein kinase ameliorates cytokine up-regulated shigatoxin-1 toxicity in human brain microvascular endothelial cells.
复制标题
抑制 p38 丝裂原激活蛋白激酶可改善人脑微血管内皮细胞中细胞因子上调的 Shigatoxin-1 毒性。
DOI：
10.1086/427188
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Kohan,DonaldE
中科院分区：
文献类型：
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作者：
Stricklett,PeterK;Hughes,AlisaK;Kohan,DonaldE
溶血性尿毒综合征（HUS）的脑损伤可能是由炎症细胞因子上调内皮细胞对志贺毒素（Stx）的敏感性而引起的。本研究调查是否可以通过抑制候选信号转导通路来改善炎症细胞因子上调的Stx毒性。暴露于肿瘤坏死因子（TNF）的人脑内皮细胞（HBECs）大大增加了Stx-1和Stx-2的细胞毒性，这是通过抑制p38丝裂原活化蛋白激酶（MAPK），但不是c-Jun激酶。SB 203580是一种p38 MAPK的特异性抑制剂，可降低TNF刺激的HBEC中Stx的细胞毒性、TNF刺激的125 Stx-1与完整HBEC的结合、Gb 3（半乳糖α 1，4、半乳糖β 1，4、葡萄糖神经酰胺）（Stx受体）的细胞含量以及TNF刺激的Gb 3合酶和葡萄糖神经酰胺合酶活性，但不影响乳糖神经酰胺合酶活性或mRNA含量。因此，抑制p38 MAPK实质上降低了Stx受体合成和细胞表面表达的炎性细胞因子上调，从而降低了Stx细胞毒性。抑制p38 MAPK可能对HUS具有治疗益处。
Brain injury in hemolytic-uremic syndrome (HUS) may be enhanced by inflammatory cytokine up-regulation of endothelial cell sensitivity to shigatoxin (Stx). The present study investigated whether inflammatory cytokine up-regulation of Stx toxicity could be ameliorated by inhibiting candidate signal transduction pathways. Exposure of human brain endothelial cells (HBECs) to tumor necrosis factor (TNF) greatly increased Stx-1 and Stx-2 cytotoxicity; this was reduced by inhibition of p38 mitogen-activated protein kinase (MAPK), but not c-Jun kinase. SB203580, a specific inhibitor of p38 MAPK, reduced TNF-stimulated Stx cytotoxicity in HBECs, TNF-stimulated125Stx-1 binding to intact HBECs, the cellular content of Gb3 (galactose α 1,4, galactose β 1,4, glucose-ceramide) (the Stx receptor), and TNF-stimulated Gb3 synthase and glucosylceramide synthase activities but did not affect lactosylceramide synthase activities or mRNA content. Thus, inhibition of p38 MAPK substantially reduces inflammatory cytokine up-regulation of Stx-receptor synthesis and cell-surface expression, thereby decreasing Stx cytotoxicity. Inhibition of p38 MAPK may be of therapeutic benefit in HUS.