Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-κB activation via EGFR transactivation in a lung epithelial cell line
Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-κB activation via EGFR transactivation in a lung epithelial cell line
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DOI：
10.1152/ajplung.00471.2005
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发表时间：
2006-09-01
影响因子：
4.9
通讯作者：
Kim, K. Chul
中科院分区：
文献类型：
--
作者：
Kuwahara, Ippei;Lillehoj, Erik P.;Kim, K. Chul
本研究探讨了中性粒细胞弹性酶（neutropil elastase， NE）对A549人肺癌细胞IL-8表达的调控作用及其机制。ne处理的细胞在培养基中的IL-8蛋白水平明显高于单独用载体处理的细胞。放线菌素D阻断基因转录表明，NE通过增加mRNA表达刺激IL-8合成，实时RT-PCR证实了这一点。NE激活了IL-8启动子，但没有改变其mRNA的稳定性，证实蛋白酶通过增加基因转录诱导IL-8合成。利用化学抑制剂和突变基因构建对抗各种信号转导成分的结果似乎表明，线性信号通路涉及pkc - δ ->双氧化酶1 ->活性氧-> tnf - α转换酶-> EGF受体-> p38 -> NF-kappa B激活ne活化的IL-8基因表达。NF-kappa B潜在结合位点位于IL-8启动子的-82和-69核苷酸之间，是ne诱导IL-8转录所必需的。我们得出结论，NE通过EGFR反激活p38/NF-kappa B激活来增加IL-8的转录。
In this study, we investigated the regulation and mechanism of IL-8 expression by A549 human lung carcinoma cells treated with neutrophil elastase (NE). NE-treated cells exhibited significantly higher IL-8 protein levels in culture media compared with cells treated with vehicle alone. Blocking of gene transcription with actinomycin D suggested that NE stimulated IL-8 synthesis via increased mRNA expression, which was verified by real-time RT-PCR. NE activated the IL-8 promoter but did not alter the stability of its mRNA, confirming that the protease induced IL-8 synthesis through increased gene transcription. The results from the use of chemical inhibitors and mutant gene constructs against various signal transduction components seem to suggest the linear signaling pathway involving the activation of PKC-delta -> dual oxidase 1 -> reactive oxygen species -> TNF-alpha-converting enzyme -> EGF receptor -> p38 -> NF-kappa B for NE-activated IL-8 gene expression. A NF-kappa B potential binding site, located between nucleotides -82 and -69 of the IL-8 promoter, was identified as necessary for NE-induced IL-8 transcription. We conclude that NE increases IL-8 transcription through p38/NF-kappa B activation via EGFR transactivation.