Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-κB-mediated transcription
Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-κB-mediated transcription
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DOI：
10.1074/jbc.274.14.9707
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发表时间：
1999-04-02
影响因子：
4.8
通讯作者：
Johnston, SL
中科院分区：
文献类型：
--
作者：
Papi, A;Johnston, SL
病毒感染，其中大部分是鼻病毒感染，是哮喘恶化的主要原因。治疗效果不理想，发病机制尚不清楚。下呼吸道淋巴细胞和嗜酸性粒细胞的招募和激活有很强的相关性，但调节这些过程的机制尚不清楚。细胞间黏附分子-1(ICAM-1)在哮喘的呼吸道炎性细胞募集中起核心作用，是90%鼻病毒的细胞受体。我们推测鼻病毒感染下呼吸道上皮细胞可能诱导ICARI-1的表达，促进炎症细胞的浸润和鼻病毒感染。因此，我们研究了鼻病毒感染对呼吸道上皮细胞ICAM-1表达和调控的影响，以确定治疗病毒诱导的哮喘恶化的新靶点。我们观察到鼻病毒感染原代支气管上皮细胞和A549呼吸道上皮细胞株分别使ICAM-1细胞表面表达增加12倍和3倍以上。然后，我们研究了在A549细胞中这种诱导的机制，并观察到鼻病毒诱导ICAM-1启动子活性和ICAM-1mRNA转录。鼻病毒对ICAM-1启动子活性的诱导主要依赖于ICAM-1启动子上-187/-178核因子-kappa B结合位点上NP-kappa B蛋白的上调。鼻病毒诱导的结合蛋白的主要成分是核因子-kappa B p65同源或异源二聚体。这些研究确定ICAM-1和NF-kappa B是开发病毒诱导的哮喘恶化治疗干预措施的新靶点。
Virus infections, the majority of which are rhinovirus infections, are the major cause of asthma exacerbations. Treatment is unsatisfactory, and the pathogenesis unclear. Lower airway lymphocyte and eosinophil recruitment and activation are strongly implicated, but the mechanisms regulating these processes are unknown. Intercellular adhesion molecule-1 (ICAM-1) has a central role in inflammatory cell recruitment to the airways in asthma and is the cellular receptor for 90% of rhinoviruses. We hypothesized that rhinovirus infection of lower airway epithelium might induce ICARI-1 expression, promoting both inflammatory cell infiltration and rhinovirus infection. We therefore investigated the effect of rhinovirus infection on respiratory epithelial cell ICAM-1 expression and regulation to identify new targets for treatment of virus-induced asthma exacerbations. We observed that rhinovirus infection of primary bronchial epithelial cells and the A549 respiratory epithelial cell line increased ICAM-1 cell surface expression over 12- and 3-fold, respectively. We then investigated the mechanisms of this induction in A549 cells and observed rhinovirus-induction of ICAM-1 promoter activity and ICAM-1 mRNA transcription. Rhinovirus induction of ICAM-1 promoter activity was critically dependent upon up-regulation of NP-kappa B proteins binding to the -187/-178 NF-kappa B binding site on the ICAM-1 promoter. The principal components of the rhinovirus-induced binding proteins were NF-kappa B p65 homo- or heterodimers. These studies identify ICAM-1 and NF-kappa B as new targets for the development of therapeutic interventions for virus-induced asthma exacerbations.