PROTEIN-KINASE-C INHIBITORS BLOCK THE ENHANCED EXPRESSION OF INTERCELLULAR-ADHESION MOLECULE-1 ON ENDOTHELIAL-CELLS ACTIVATED BY INTERLEUKIN-1, LIPOPOLYSACCHARIDE AND TUMOR-NECROSIS-FACTOR
PROTEIN-KINASE-C INHIBITORS BLOCK THE ENHANCED EXPRESSION OF INTERCELLULAR-ADHESION MOLECULE-1 ON ENDOTHELIAL-CELLS ACTIVATED BY INTERLEUKIN-1, LIPOPOLYSACCHARIDE AND TUMOR-NECROSIS-FACTOR
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DOI：
10.1016/0006-291x(90)91587-i
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发表时间：
1990-11-15
影响因子：
3.1
通讯作者：
WANCEWICZ, EV
中科院分区：
文献类型：
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作者：
LANE, TA;LAMKIN, GE;WANCEWICZ, EV
白细胞介素1 （IL-1）、细菌脂多糖（LPS）和肿瘤坏死因子（tnf . α）增强内皮细胞（EC）对中性粒细胞（PMN）的粘附特性。这部分是由细胞间粘附分子1 （ICAM-1）在EC上的上调介导的。Phorbol酯可以激活蛋白激酶c （PKC）并增强EC对PMN的粘附特性，同时也可以上调e上ICAM-1的表达。我们研究了PKC抑制剂对人脐静脉EC (HUVEC) ICAM-1表达的影响。Staurosporine （STS）和1-（5-异喹啉基磺酰基）-2-甲基哌嗪（H-7）可阻止HUVEC对ICAM-1表达和PMN粘附的炎症介质依赖性刺激（STS的ID50 = 2.7-2.9 μ m； H-7的ID50 = 7.6-8.8 μ m）。抑制作用与剂量和时间有关，与HUVEC毒性无关。STS类似物K25a和H-7类似物H-7对ICAM-1上调和粘附促进的抑制作用较弱。HUVEC长期暴露于肉豆蔻酸酯佛波酯中，可下调PKC活性，并抑制该制剂和IL-1随后对ICAM-1的上调。我们得出结论，炎症介质诱导的HUVEC表达ICAM-1的刺激和粘附特性的促进部分是由PKC的激活介导的。
Interleukin 1 (IL-1), bacterial lipopolysaccharide (LPS) and tumor necrosis factor (TNF.alpha.) enhance the adherence properties of endothelial cells (EC) for neutrophils (PMN). This is mediated in part by the up-regulation of Intercellular Adhesion Molecule 1 (ICAM-1) on EC. Phorbol esters, which activate protein kinase c (PKC) and enhance the adherence properties of EC for PMN also up-regulate the ICAM-1 expression on E. We investigated the effect of PKC inhibitors on ICAM-1 expression of human umbilical vein EC (HUVEC). Staurosporine (STS) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) prevented inflammatory mediator-dependent stimulation of both ICAM-1 expression and PMN adherence by HUVEC (ID50 for STS = 2.7-2.9 .mu.M; for H-7 = 7.6-8.8 .mu.M). Inhibition was dose and time-dependent and was not due to HUVEC toxicity. The STS analog K25a and the H-7 analog H-7 were less potent inhibitors of ICAM-1 up-regulation and adherence promotion. Prolonged exposure of HUVEC to phorbol myristate acetate down-regulated PKC activity and inhibited subsequent ICAM-1 up-regulation by this agent and by IL-1. We conclude that inflammatory mediator induced stimulation of HUVEC expression of ICAM-1 and promotion of adherence properties are mediated in part by activation of PKC.