1,721,207 research outputs found
Rhinovirus Infection Induces Expression of Its Own Receptor Intercellular Adhesion Molecule 1 (ICAM-1) via Increased NF-κB-mediated Transcription
No full textVirus 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
Respiratory Epithelial Cell Expression of Vascular Cell Adhesion Molecule-1 and Its Up-regulation by Rhinovirus Infection via NF-κB and GATA Transcription Factors
No full textVirus 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 exacerbatio
Corticosteroids inhibit rhinovirus-induced intercellular adhesion molecule-1 up-regulation and promoter activation on respiratory epithelial cells
No full textBACKGROUND: Rhinoviruses are associated with the majority of asthma exacerbations. To date, the pathogenesis of virus-induced asthma exacerbations is still unclear, and no safe effective therapy is available. Intercellular adhesion molecule-1 (ICAM-1) has a central role in inflammatory cell recruitment to the airways in asthma and is the receptor for 90% of rhinoviruses. We have previously shown that rhinovirus infection of lower airway epithelium induces ICAM-1 expression by a transcriptional mechanism that is critically nuclear factor-kappaB-dependent. OBJECTIVE: The purpose of this study was to investigate the effect of systemic (hydrocortisone [HC], dexamethasone [DM]) and topical (mometasone furoate [MF]) corticosteroids on rhinovirus-induced ICAM-1 up-regulation. METHODS: Cultured primary bronchial or transformed (A549) respiratory epithelial cells were pretreated with corticosteroids for 16 hours and infected with rhinovirus type 16 for 8 hours. ICAM-1 surface expression was evaluated by flow cytometry. In A549 cells ICAM-1 messenger RNA was evaluated by specific reverse transcription-PCR and promoter activation by chloramphenicol acetyltransferase assay. RESULTS: We observed inhibition of rhinovirus-induced ICAM-1 up-regulation with corticosteroid pretreatment in both primary bronchial epithelial and A549 cells. In A549 cells systemic and topical corticosteroids demonstrated a dose-dependent inhibition with similar efficacy (inhibitory concentration 50% 10(-10) mol/L, 10(-11) mol/L, and 10(-11) mol/L for HC, DM, and MF respectively). MF also inhibited ICAM-1 messenger RNA induction by rhinovirus infection in a dose-dependent manner. MF completely inhibited rhinovirus-induced ICAM-1 promoter activation. HC, DM, and MF had no direct effect on rhinovirus infectivity and replication in cultured cells. CONCLUSION: Corticosteroids decrease rhinovirus-induced ICAM-1 up-regulation in respiratory epithelial cells and modulate pretranscriptional mechanisms. This effect may be important for the therapeutic control of virus-induced asthma exacerbation
A defective type 1 response to rhinovirus in atopic asthma
No full textBACKGROUND: Rhinoviruses (RVs) are the most frequent precipitants of the common cold and asthma exacerbations, but little is known about the immune response to these viruses and its potential implications in the pathogenesis of asthma. METHODS: Peripheral blood mononuclear cells (PBMC) from patients with atopic asthma and normal subjects were exposed to live or inactivated RV preparations. Levels of interferon (IFN)gamma and interleukins IL-12, IL-10, IL-4, IL-5 and IL-13 were evaluated in the culture supernatants with specific immunoassays. RESULTS: Exposure of PBMC to RVs induced the production of IFNgamma, IL-12, IL-10, and IL-13. Cells from asthmatic subjects produced significantly lower levels of IFNgamma and IL-12 and higher levels of IL-10 than normal subjects. IL-4 was induced only in the asthmatic group, while the IFNgamma/IL-4 ratio was more than three times lower in the asthmatic group. CONCLUSIONS: This evidence suggests that the immune response to RVs is not uniquely of a type 1 phenotype, as previously suggested. The type 1 response is defective in atopic asthmatic individuals, with a shift towards a type 2 phenotype in a way similar, but not identical, to their aberrant response to allergens. A defective type 1 immune response to RVs may be implicated in the pathogenesis of virus induced exacerbations of asthma
Mechanisms of rhinovirus-induced asthma
No full textSeveral epidemiological studies using sensitive detection methodologies have confirmed that the majority of acute asthma exacerbations follow upper respiratory tract infections – common colds. Most of these colds are due to human rhinoviruses (RVs). RVs are able to reach and replicate in epithelial cells of the lower airways and can activate these cells to produce pro-inflammatory mediators. Under some circumstances, RVs can also become cytotoxic to the epithelium. Atopic asthmatic individuals produce less interferon-γ and more interleukin-10 than normal subjects in response to RV infection. Symptom severity as well as viral shedding after experimental RV infection, is inversely correlated with ‘atopic’ status, expressed as the interferon-γ to interleukin-5 ratio. Expression of co-stimulatory molecules on immune cells is also affected in atopic asthmatics, suggesting an aberrant immune response to RV that may lead to suboptimal viral clearance and viral persistence. Some of the above effects can be reversed in vitro by corticosteroids, second-generation antihistamines or anti-oxidants; however, the optimal strategy for treating acute asthma exacerbations requires further research at both mechanistic and clinical levels
Rhinoviruses induce interleukin-8 mRNA and protein production in human monocytes
No full textRhinoviruses are important upper respiratory pathogens that are strongly associated with asthma exacerbations. However, the inflammatory response to rhinovirus infection is poorly understood. Interleukin (IL)-8 has been implicated in the pathogenesis of respiratory viral infections and asthma. Rhinovirus-induced IL-8 release and mRNA induction were examined in peripheral blood mononuclear cells (PBMC). Rhinoviruses induced IL-8 release for up to 7 days after inoculation onto PBMC. This was associated with an increase in IL-8 mRNA expression that peaked 48 h after exposure to the virus. IL-8 protein production was reduced by UV inactivation of the virus and abolished by preventing virus-receptor binding. Although rhinovirus replication was not demonstrated in PBMC, low-grade productive infection was shown in the human monocyte cell line THP-1. Rhinovirus induction of IL-8 in monocytes or airway macrophages may be important in the pathogenesis of rhinovirus-induced asthma exacerbation
Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.
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Interleukin-4 Modulates Rhinovirus Replication and Antiviral Immune Response in Respiratory Epithelial Cells
No full textReducing agents inhibit rhinovirus-induced up-regulation of the rhinovirus receptor intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells
No full textRhinoviruses are the major cause of common colds and of asthma exacerbations. Intercellular adhesion molecule-1 (ICAM-1) has a central role in airway inflammation and is the receptor for 90% of rhinoviruses. Rhinovirus infection of airway epithelium induces ICAM-1. Because redox state is directly implicated in inflammatory responses via molecular signaling mechanisms, here we studied the effects of reducing agents on rhinovirus-induced ICAM-1 expression, mRNA up-regulation, promoter activation, and nuclear factor activation. To investigate the effects of rhinovirus infection on the intracellular redox balance, we also studied whether rhinovirus infection triggers the production of reactive oxygen species. We found that reduced (GSH) but not oxidized (GSSG) glutathione (1-100 microM) inhibited in a dose-dependent manner rhinovirus-induced ICAM-1 up-regulation and mRNA induction in primary bronchial and A549 respiratory epithelial cells. GSH but not GSSG also inhibited rhinovirus-induced ICAM-1 promoter activation and rhinovirus-induced NF-kB activation. In parallel, we found that rhinovirus infection induced a rapid increase of intracellular superoxide anion that was maximal at the time of NF-kB activation. This oxidant generation was completely inhibited by GSH. We conclude that redox-mediated intracellular pathways represent an important target for the therapeutic control of rhinovirus-induced disease
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