Tumor necrosis factor α-induced activation of downstream NF-κB site of the promoter mediates epithelial ICAM-1 expression and monocyte adhesion:: Involvement of PKCα, tyrosine kinase, and IKK2, but not MAPKs, pathway
Tumor necrosis factor α-induced activation of downstream NF-κB site of the promoter mediates epithelial ICAM-1 expression and monocyte adhesion:: Involvement of PKCα, tyrosine kinase, and IKK2, but not MAPKs, pathway
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DOI：
10.1016/s0898-6568(01)00171-1
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发表时间：
2001-08-01
影响因子：
4.8
通讯作者：
Huang, WC
中科院分区：
文献类型：
--
作者：
Chen, CC;Chou, CY;Huang, WC
肿瘤坏死因子-α诱导人A549上皮细胞表达细胞间黏附分子-1(ICAM-1)，免疫荧光染色证实这一结果。ICAM-1表达增强可增加U937细胞与A549细胞的粘附力。酪氨酸激酶抑制剂(Genistein或Tyrphostin 23)或磷脂酰胆碱特异性磷脂酶C(PC-PLC)抑制剂(D609)可减弱肿瘤坏死因子-α诱导的ICAM-1的表达。肿瘤坏死因子-α可增加蛋白激酶C(PKC)的活性，这种作用可被D609抑制。PKC抑制剂(星形孢子素、Ro31-8220、Calphostin C或GO 6976)也可抑制肿瘤坏死因子-α诱导的反应。PKC激活剂12-O-十四烷基酚-13-乙酸酯(TPA)可刺激ICAM-1的表达，此作用可被染料木素或酪磷蛋白23所抑制。用肿瘤坏死因子-α处理细胞后，p44/42NL、MAPK、p38和JNK被激活。然而，MEK抑制剂PD 98059和p38抑制剂SB 203580均不影响肿瘤坏死因子-α诱导的细胞间黏附分子-1表达。细胞通透性神经酰胺类似物C-2神经酰胺也能刺激这三种MAPK的激活，但对ICAM-1的表达没有影响。肿瘤坏死因子-α可增强核因子-kappaBDNA-蛋白结合和细胞间黏附分子-1启动子活性，这些作用可被D609、Calphostin C或Tyrphostin 23抑制，但不能被PD 98059或SB 203580所抑制。TPA还可刺激NF-kappaB DNA蛋白结合和ICAM-1启动子活性，这些作用可被金雀异黄素或酪氨酸蛋白23抑制。显性负性PKCα或IKK2可抑制肿瘤坏死因子-α或TPA诱导的ICAM-1启动子活性，但不能抑制IKK1突变。肿瘤坏死因子-α和TPA对IKK活性均有刺激作用，而Ro 31-8220或Tyrphostin 23可抑制这种作用。这些结果表明，在A549细胞中，肿瘤坏死因子-α激活PC-PLC，诱导PKC-α和蛋白酪氨酸激酶的激活，从而刺激ICAM-1启动子中的IKK2和NF-kappaB，进而启动ICAM-1的表达和中性粒细胞的黏附。然而，p44/42 NL、MAPK、p38和JNK的激活并不参与这一事件。(C)2001 Elsevier Science Inc.保留所有权利。
TNF-alpha induced an increase in intercellular adhesion molecule-1 (ICAM-1) expression in human A549 epithelial cells and immuno fluorescence staining confirmed this result. The enhanced ICAM-1 expression was shown to increase the adhesion of U937 cells to A549 cells. Tyrosine kinase inhibitors (genistein or tyrphostin 23) or phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor (D 609) attenuated TNF-alpha -induced ICAM-1 expression. TNF-alpha produced an increase in protein kinase C (PKC) activity and this effect was inhibited by D 609. PKC inhibitors (staurosporine, Ro 31-8220, calphostin C, or Go 6976) also inhibited TNF-alpha -induced response. 12-O-Tetradecanoylphorb ol-13-acetate (TPA), a PKC activator, stimulated ICAM-1 expression, this effect was inhibited by genistein or tyrphostin 23. Treatment of cells with TNF-alpha resulted in stimulation of p44/42 NL, MAPK, p38, and JNK. However, TNF-alpha -induced ICAM-1 expression was not affected by either MEK inhibitor, PD 98059, or p38 inhibitor, SB 203580. A cell-permeable ceramide analog, C-2 ceramide, also stimulated the activation of these three MAPKs, but had no effect on ICAM-1 expression. NF-kappaB DNA-protein binding and ICAM-1 promoter activity were enhanced by TNF-alpha and these effects were inhibited by D 609, calphostin C, or tyrphostin 23, but not by PD 98059 or SB 203580. TPA also stimulated NF-kappaB DNA-protein binding and ICAM-1 promoter activity, these effects being inhibited by genistein or tyrphostin 23. TNF-alpha- or TPA-induced ICAM-1 promoter activity was inhibited by dominant negative PKC alpha or IKK2, but not IKK1 mutant. IKK activity was stimulated by both TNF-alpha and TPA, and these effects were inhibited by Ro 31-8220 or tyrphostin 23. These data suggest that, in A549 cells, TNF-alpha activates PC-PLC to induce activation of PKC alpha and protein tyrosine kinase, resulting in the stimulation of IKK2 and NF-kappaB in the ICAM-1 promoter, then initiation of ICAM-1 expression and neutrophil adhesion. However, activation of p44/42 NL, MAPK, p38, and JNK is not involved in this event. (C) 2001 Elsevier Science Inc. All rights reserved.