Adenovirus type 7 induces interleukin-8 production via activation of extracellular regulated kinase 1/2
Adenovirus type 7 induces interleukin-8 production via activation of extracellular regulated kinase 1/2
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DOI：
10.1128/jvi.75.14.6450-6459.2001
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发表时间：
2001-07-01
影响因子：
5.4
通讯作者：
Metcalf, JP
中科院分区：
文献类型：
--
作者：
Alcorn, MJ;Booth, JL;Metcalf, JP
腺病毒血清7型(Ad7)感染经常导致下呼吸道肺炎，并与严重的肺部炎症和中性粒细胞浸润有关。早期的研究表明，在Ad7感染后，肺上皮细胞释放促炎细胞因子，特别是白介素8(IL-8)。然而，Ad7诱导IL-8的作用机制尚不清楚。我们利用A549上皮细胞模型系统探讨了Ras/Raf/MEK/Erk通路在Ad7相关IL-8诱导中的作用。我们发现Ad7感染诱导了上皮细胞来源的ERK的快速激活。MEK特异性抑制剂PD98059和U0126可阻断感染Ad7后ERK的激活和IL-8的释放。PD98059的治疗是细胞抑制的，没有细胞毒性，因为在药物去除后，处理的细胞重新获得磷酸化ERK和分泌IL-8的能力。突变形式的RAS在A549上皮细胞中的表达阻断了IL-8启动子活性的诱导，而MEK抑制剂则阻断了IL-8mRNA的诱导。这些结果表明，Ras/Raf/MEK/Erk通路是Ad7诱导IL-8所必需的，并且诱导发生在转录水平。此外，ERK激活和IL-8诱导的动力学表明，早期的病毒事件，如受体结合，可能是所观察到的炎症反应的原因。
Infection with adenovirus serotype 7 (Ad7) frequently causes lower respiratory pneumonia and is associated with severe lung inflammation and neutrophil infiltration. Earlier studies indicated release of proinflammatory cytokines, specifically interleukin-8 (IL-8), by pulmonary epithelial cells following infection by Ad7. However, the mechanism of IL-8 induction by Ad7 is unclear. We have explored the role of the Ras/Raf/MEK/Erk pathway in the Ad7-associated induction of IL-8 using a model system of A549 epithelial cells. We found that Ad7 infection induced a rapid activation of epithelial cell-derived Erk. The MEK-specific inhibitors PD98059 and U0126 blocked Erk activation and release of IL-8 following infection with Ad7. Treatment with PD98059 is cytostatic and not cytotoxic, as treated cells regain the ability to phosphorylate Erk and secrete IL-8 after removal of the drug. The expression of a mutated form of Ras in A549 epithelial cells blocked the induction of IL-8 promoter activity, and MEK inhibitor blocked induction of IL-8 mRNA. These results suggest that the Ras/Raf/MEK/Erk pathway is necessary for the Ad7 induction of IL-8 and that induction occurs at the level of transcription. Further, the kinetics of Erk activation and IL-8 induction suggest that an early viral event, such as receptor binding, may be responsible for the observed inflammatory response.