Indukuri Hemalatha, Castro Shawn M, Liao Sha-Mei, Feeney Lee Ann, Dorsch Marion, Coyle Anthony J, Garofalo Roberto P, Brasier Allan R, Casola Antonella
Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555-0366, USA.
Virology. 2006 Sep 15;353(1):155-65. doi: 10.1016/j.virol.2006.05.022. Epub 2006 Jun 27.
Respiratory syncytial virus (RSV)-induced chemokine gene expression occurs through the activation of a subset of transcription factors, including Interferon Regulatory Factor (IRF)-3. In this study, we have investigated the signaling pathway leading to RSV-induced IRF-3 activation and whether it is mediated by intracellular reactive oxygen species (ROS) generation. Our results show that RSV infection induces expression and catalytic activity of IKKepsilon, a noncanonical IKK-like kinase. Expression of a kinase-inactive IKKepsilon blocks RSV-induced IRF-3 serine phosphorylation, nuclear translocation and DNA-binding, leading to inhibition of RANTES gene transcription, mRNA expression and protein synthesis. Treatment of alveolar epithelial cells with antioxidants or with NAD(P)H oxidase inhibitors abrogates RSV-induced chemokine secretion, IRF-3 phosphorylation and IKKepsilon induction, indicating that ROS generation plays a fundamental role in the signaling pathway leading to IRF-3 activation, therefore, identifying a novel molecular target for the development of strategies aimed to modify the inflammatory response associated with RSV infection of the lung.
呼吸道合胞病毒（RSV）诱导的趋化因子基因表达是通过激活包括干扰素调节因子（IRF）-3在内的一组转录因子来实现的。在本研究中，我们调查了导致RSV诱导的IRF-3激活的信号通路，以及它是否由细胞内活性氧（ROS）生成介导。我们的结果表明，RSV感染可诱导非典型IKK样激酶IKKε的表达和催化活性。激酶失活的IKKε的表达可阻断RSV诱导的IRF-3丝氨酸磷酸化、核转位和DNA结合，从而导致RANTES基因转录、mRNA表达和蛋白质合成受到抑制。用抗氧化剂或NAD（P）H氧化酶抑制剂处理肺泡上皮细胞可消除RSV诱导的趋化因子分泌、IRF-3磷酸化和IKKε诱导，这表明ROS生成在导致IRF-3激活的信号通路中起基本作用，因此，为旨在改变与肺部RSV感染相关的炎症反应的策略开发确定了一个新的分子靶点。
