Respiratory epithelial cell expression of vascular cell adhesion molecule-1 and its up-regulation by rhinovirus infection via NF-kappaB and GATA transcription factors.
Virus infections, the majority of which are rhinovirus infections, are the major cause of asthma exacerbations. Asthma now affects one-fifth of the population, yet treatment of exacerbations is unsatisfactory, and the pathogenesis is unclear. Intraepithelial lymphocyte and eosinophil infiltration and activation are strongly implicated, but the mechanisms regulating these processes are unknown. We hypothesized that lower airway epithelial expression of vascular cell adhesion molecule-1 (VCAM-1) may be important in intraepithelial inflammation and that expression would be induced by pro-inflammatory stimuli and rhinovirus infection. We investigated respiratory epithelial cell VCAM-1 expression and its regulation to identify new targets for treatment of virus-induced asthma exacerbations. We observed constitutive respiratory epithelial cell VCAM-1 expression and that rhinovirus infection, but no other pro-inflammatory stimuli tested increased VCAM-1 cell surface expression in respiratory epithelial cell lines and primary bronchial epithelial cells. We then observed rhinovirus induction of VCAM-1 mRNA expression, promoter activity, and mRNA transcription. Rhinovirus induction of VCAM-1 promoter activity was critically dependent on up-regulation of proteins binding to the -254/-251 and -239/-236 GATA-binding sites and to the -72/-63 and -57/-48 NF-kappaB-binding sites in the VCAM-1 promoter. These studies identify VCAM-1 and the NF-kappaB and GATA transcription factor families as new targets for development of therapeutic interventions for virus-induced asthma exacerbations.
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University Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom.
Johnston
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D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D006367:HeLa Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism* / Q000821:virology; D012229:Rhinovirus / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1