Interleukin-1β stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells
Interleukin-1β stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells
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DOI：
10.1038/sj.onc.1207867
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发表时间：
2004-08-26
期刊：
影响因子：
8
通讯作者：
Jung, YD
中科院分区：
文献类型：
--
作者：
Hwang, YS;Jeong, M;Jung, YD
最近的研究表明，白细胞介素8（IL-8）的表达与人类胃癌的血管分布直接相关。本研究探讨IL-1β对人胃癌TMK-1细胞IL-8表达的影响及其潜在的信号转导通路。 IL-1β 以时间和浓度依赖性方式诱导 IL-8 表达。 IL-1β 诱导细胞外信号调节激酶 1/2 和 P38 丝裂原激活蛋白激酶 (MAPK) 的激活，但不诱导 c-jun 氨基末端激酶和 Akt 的激活。 MEK-1 (PD980590) 和 P38 MAPK (SB203580) 的特异性抑制剂被发现可抑制 IL-8 表达和 IL-8 启动子活性。编码突变型MEK-1和P38 MAPK的载体的表达导致IL-8启动子活性降低。 IL-1β 还诱导活性氧 (ROS) 的产生。 N-乙酰半胱氨酸 (NAC) 阻止 IL-1β 诱导的 ROS 产生和 IL-8 表达。此外，外源H2O2可以诱导IL-8的表达。对 IL-8 启动子的缺失和定点突变研究表明，激活蛋白 1 (AP-1) 和核因子 (NF)-kappaB 位点是 IL-1β 诱导的 IL-8 转录所必需的。电泳迁移率变动测定证实 IL-1beta 增加了 AP-1 和 NF-kappaB 的 DNA 结合活性。抑制剂（PD980590、SB203580）和ROS清除剂（NAC）研究表明，转录因子AP-1和NF-kappaB的上游信号传导分别是MAPK和ROS。用IL-1β预处理的TMK-1细胞的条件培养基可以显着刺激HUVEC的体外生长，并且这种效应被IL-8中和抗体部分消除。以上结果提示MAPK-AP-1和ROS-NF-kappaB信号通路参与IL-1β诱导的IL-8表达，并且这些旁分泌信号通路诱导内皮细胞增殖。
Recent studies have suggested that the expression of interleukin-8 (IL-8) directly correlates with the vascularity of human gastric carcinomas. In this study, the effect of IL-1beta on IL-8 expression in human gastric cancer TMK-1 cells and the underlying signal transduction pathways were investigated. IL-1beta induced the IL-8 expression in a time- and concentration-dependent manner. IL-1beta induced the activation of extracellular signal-regulated kinases-1/2 and P38 mitogen-activated protein kinase ( MAPK), but not the activation of c-jun amino-terminal kinse and Akt. Specific inhibitors of MEK-1 (PD980590) and P38 MAPK (SB203580) were found to suppress the IL-8 expression and the IL-8 promoter activity. Expression of vectors encoding a mutated-type MEK-1 and P38 MAPK resulted in decrease in the IL-8 promoter activity. IL-1beta also induced the production of reactive oxygen species (ROS). N-acetyl cysteine (NAC) prevented the IL-1beta-induced ROS production and IL-8 expression. In addition, exogenous H2O2 could induce the IL-8 expression. Deletional and site-directed mutagenesis studies on the IL-8 promoter revealed that activator protein-1 (AP-1) and nuclear factor (NF)-kappaB sites were required for the IL-1beta-induced IL-8 transcription. Electrophoretic mobility shift assay confirmed that IL-1beta increased the DNA-binding activity of AP-1 and NF-kappaB. Inhibitor ( PD980590, SB203580) and ROS scavenger ( NAC) studies revealed that the upstream signalings for the transcription factors AP-1 and NF-kappaB were MAPK and ROS, respectively. Conditioned media from the TMK-1 cells pretreated with IL-1beta could remarkably stimulate the in vitro growth of HUVEC and this effect was partially abrogated by IL-8-neutralizing antibodies. The above results suggest that MAPK-AP-1 and ROS-NF-kappaB signaling pathways are involved in the IL-1beta-induced IL-8 expression and that these paracrine signaling pathways induce endothelial cell proliferation.