Abstract
BackgroundExacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV) are the predominant virus type. Airway smooth muscle is important in asthma pathogenesis, however little is known about the potential interaction of RV and human airway smooth muscle cells (HASM). We hypothesised that rhinovirus induction of inflammatory cytokine release from airway smooth muscle is augmented and differentially regulated in asthmatic compared to normal HASM cells.MethodsHASM cells, isolated from either asthmatic or non-asthmatic subjects, were infected with rhinovirus. Cytokine production was assayed by ELISA, ICAM-1 cell surface expression was assessed by FACS, and the transcription regulation of IL-6 was measured by luciferase activity.ResultsRV-induced IL-6 release was significantly greater in HASM cells derived from asthmatic subjects compared to non-asthmatic subjects. This response was RV specific, as 5% serum- induced IL-6 release was not different in the two cell types. Whilst serum stimulated IL-8 production in cells from both subject groups, RV induced IL-8 production in only asthmatic derived HASM cells. The transcriptional induction of IL-6 was differentially regulated via C/EBP in the asthmatic and NF-κB + AP-1 in the non-asthmatic HASM cells.ConclusionThis study demonstrates augmentation and differential transcriptional regulation of RV specific innate immune response in HASM cells derived from asthmatic and non-asthmatics, and may give valuable insight into the mechanisms of RV-induced asthma exacerbations.
Highlights
Exacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV) are the predominant virus type
Since it has been previously suggested that RV infection of human airway smooth muscle cells (HASM) cells mediates cytokine production [22], and since major differences in innate responses of bronchial epithelial cells from asthmatic and normal subjects to RV infection have been recently demonstrated [10], we hypothesised that RV induction of inflammatory cytokine release is augmented in primary HASM cells from asthmatic compared with normal subjects. Having found this to be the case, and with the knowledge that a transcription factor which can bind to the IL-6 promoter region, C/EBPα, is absent from asthmatic but not normal HASM cells [24] we investigated transcriptional regulation of IL6 to determine whether its expression is differentially regulated in asthmatic compared to normal HASM cells
Infection with RV-16 (MOI of 4) induced significant cell death in HASM cells derived from both asthmatic and non-asthmatic subjects, the viability of asthmatic cells was reduced to 45 ± 13% and non-asthmatic cells to 52 ± 11% by 24 hours post infection (p < 0.05 RV versus control, n = 3 for both)
Summary
Whilst the purpose of this study was not to determine the kinetics of RV replication within HASM cells, the titer of RV within the cell culture media was measured at 24 hours post-infection
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