Respiratory Epithelial Cell Expression of Vascular Cell Adhesion Molecule-1 and Its Up-regulation by Rhinovirus Infection via NF-κB and GATA Transcription Factors

Abstract

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-B-binding sites in the VCAM-1 promoter. These studies identify VCAM-1 and the NF-B and GATA transcription factor families as new targets for development of therapeutic interventions for virus-induced asthma exacerbations.

Role of p38 Mitogen-Activated Protein Kinase in Rhinovirus-Induced Cytokine Production by Bronchial Epithelial Cells

“…The role of the NF-B transcription factor in HRV-induced IL-8 and IL-6 biosynthesis in airway epithelial cells, as well as ICAM-1 and VCAM-1 adhesion molecule expression, is well documented (10,11,13,40). Therefore, stimulation of the p38 MAP kinase pathway may be at least partially responsible for the activation of the NF-B transcription pathway in epithelial cells in response to rhinovirus infection.…”

Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies

“…GATA-6, independently or cooperatively with thyroid transcription factor-1, enhances murine surfactant protein A transcription [14,15]. In addition, rhinovirus infection of A-549 cells upregulates the expression of vascular cell adhesion molecule 1 via increased activity of members of the GATA transcription factor family [16].…”

Function of GATA Transcription Factors in Induction of Endothelial Vascular Cell Adhesion Molecule-1 by Tumor Necrosis Factor-α

“…9 They are essential for the differentiation and function of hematopoietic cells and endothelial cells as well as fetal differentiation of the cardiovascular system. 10 -12 Although several lines of evidence have provided support for the importance of the GATA element in the upstream promoter region of the VCAM-1 gene, 5,8,13,14 the specific regulatory effects exerted by the GATA factors on endothelial gene expression have yet to be elucidated. Recently, we developed a novel VCAM-1 inhibitor, K-7174, which acts through a mechanism independent of NF-B activity.…”