Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506464
Title: Regulation of human rhinovirus induced type I interferon-β, type III interferon-λ and pro-inflammatory cytokine gene expression in normal human bronchial epithelial cells
Author: Slater, Louise
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Abstract:
Asthma is an economically important disease, with exacerbations causing significant morbidity and morality. Viral infections cause ~80% of asthma exacerbations; the majority of which are attributed to rhinovirus infection. How rhinovirus infection leads to an acute asthma exacerbation is incompletely understood. The up-regulation of proinflammatory cytokines/chemokines from rhinovirus infected bronchial epithelial cells and an impaired ability of rhinovirus infected asthmatic bronchial epithelial cells to produce type I interferon-β and type III interferon-λs, are believed to contribute. This study aimed to investigate differences in the signalling requirements of rhinovirus induced pro-inflammatory cytokines/chemokines from those of IFN-β/IFN-λ. The viral pattern recognition receptors, signalling intermediates and transcription factors required by rhinovirus to induce pro-inflammatory cytokine/chemokine and IFN-β/IFN-λ expression were explored using short interfering RNA, constitutive activation/overexpression of signalling molecules and IFN-β promoter reporter mapping experiments. The viral pattern recognition receptors RIG-I, MDA5 and TLR3 were required for rhinovirus-induced pro-inflammatory cytokines IL-8/CXCL8, ENA-78/CXCL5, IL-6 RANTES/CCL5, IP-10/CXCL10 and IFN-β expression. Only MDA5 and TLR3 are required for rhinovirus-induced IFN-λ expression. Whilst having common signalling intermediates, the adaptor protein TRAF6, the kinases JNK2 and PI3Kα and the transcription factor NF-κB p65 were not required for rhinovirus-induced IFN-β/λ expression, but were required for rhinovirus induction of some/all of the proinflammatory cytokines measured. IRF3 was the only transcription factor identified to be commonly required for rhinovirus-induced expression of IFN-β and IFN-λs. These findings support the hypothesis that the induction of IFN-β/λ and pro-inflammatory cytokines/chemokines, by rhinovirus, requires one or more distinct signalling molecules, and/or transcription factors. TRAF6, JNK2, PI3Kα and NF-κB p65 are potential novel therapeutic targets for rhinovirus-induced asthma exacerbations, the inhibition of which may suppress the detrimental actions of pro-inflammatory cytokines/chemokines without inhibiting IFN-β/λ production in asthmatic bronchial epithelial cells.
Supervisor: Edwards, Michael ; Johnston, Sebastian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.506464  DOI: Not available
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