Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-κB-inducing kinases
Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-κB-inducing kinases
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DOI：
10.1152/ajplung.00031.2003
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发表时间：
2003-08-01
影响因子：
4.9
通讯作者：
Quinn, DA
中科院分区：
文献类型：
--
作者：
Li, LF;Ouyang, B;Quinn, DA
大潮气量的正压通气已被证明会导致细胞因子的释放，包括白细胞介素8。调节肺牵张诱导的细胞因子产生的机制尚不清楚。我们假设拉伸诱导的IL-8的产生依赖于有丝分裂原激活的蛋白激酶、c-jun氨基末端激酶(JNK)、p38和/或细胞外信号调节激酶(ERK)1/2的激活。我们以20周期/分钟的周期拉伸5min-2小时暴露于肺泡II型上皮细胞株A549。腺病毒介导腺病毒介导的应激活化蛋白激酶(SEK-1)和JNK的直接上游激活剂SEK-1的显性负性突变体(SEK-1)和药物JNK抑制剂II SP-600125抑制了IL-8mRNA的表达，并抑制了IL-8的产生。抑制p38和ERK1/2不影响牵张诱导的IL-8的产生。牵张诱导的核因子-kappaB和激活蛋白(AP)-1分别被核因子-kappaB抑制剂和JNK抑制剂阻断。核因子-IL-6位点对周期性拉伸诱导的IL-8启动子活性不是必需的。牵张还可诱导核因子-kappaB诱导激酶(NIK)的激活，抑制核因子-kappaB可抑制IL-8mRNA的表达和IL-8的产生。我们的结论是，牵张诱导的IL-8mRNA和IL-8产生的转录调控分别是通过激活AP-1和NF-kappaB而实现的，并且分别依赖于JNK和NIK的激活。
Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including interleukin (IL)-8. The mechanisms regulating lung stretch-induced cytokine production are unclear. We hypothesized that stretch-induced IL-8 production is dependent on the activation of the mitogen-activated protein kinases, c-Jun NH2-terminal kinases (JNK), p38, and/or extracellular signal-regulated kinase (ERK) 1/2. We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/min for 5 min-2 h. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression, and JNK activation, but only transient activation of p38 and ERK1/2. Inhibition of stretch-induced JNK activation by adenovirus-mediated gene transfer of stress-activated protein kinase (SEK-1), a dominant-negative mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP-600125 blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation NF-kappaB and activator protein (AP)-1 was blocked by NF-kappaB inhibitor and JNK inhibitor, respectively. An NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-kappaB-inducing kinase (NIK) activation, and inhibition of NF-kappaB attenuated IL-8 mRNA expression and IL-8 production. We conclude that stretch-induced transcriptional regulation of IL-8 mRNA and IL-8 production was via activation of AP-1 and NF-kappaB and was dependent on JNK and NIK activation, respectively.