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Abstract
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 ICAM-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 NF-kappaB proteins binding to the -187/-178 NF-kappaB binding site on the ICAM-1 promoter. The principal components of the rhinovirus-induced binding proteins were NF-kappaB p65 homo- or heterodimers. These studies identify ICAM-1 and NF-kappaB as new targets for the development of therapeutic interventions for virus-induced asthma exacerbations.
Highlights
Asthma is increasingly common and affects up to 30% of the population in westernized countries [1]
We have investigated mechanisms involved in rhinovirus-induced asthma exacerbations by studying the effect of rhinovirus infection on airway epithelial cell Intercellular adhesion molecule-1 (ICAM-1) expression
These studies were performed, since ICAM-1 is the receptor for 90% of rhinoviruses and is an adhesion protein that has a central role in inflammatory cell recruitment to the lower airway following rhinovirus infection
Summary
Asthma is increasingly common and affects up to 30% of the population in westernized countries [1]. Viral infections have been strongly implicated in more severe asthma exacerbations requiring hospitalization in both children and in adults [4] In all of these studies, rhinovirus infections caused around 65% of exacerbations in which a virus was identified [2,3,4]. Rhinovirus experimental infections have been reported to increase allergen-induced eosinophil numbers in bronchial lavage fluid in atopic rhinitic subjects, while no change in eosinophil numbers was observed in normal subjects [8], and to increase eosinophil products in sputum supernatants in asthmatic subjects [9] These data combined strongly suggest that rhinovirus-induced bronchial lymphocyte and eosinophil infiltration and activation are probably very important mechanisms in virus-induced asthma exacerbations. Rhinoviruses are capable of prolonged, noncytolytic infection of respiratory epithelial cells and induce production of proinflammatory cy-
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