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dc.contributor.authorFong, Carol Ho Yan
dc.description.abstractRecent research has revealed a role of NF-B in the resolution of inflammation. Using Cre-lox mediated gene targeting, IKK was selectively deleted in macrophages (IKKβ∆Mye). From in vitro studies, LPS stimulated IKKMye macrophages increased STAT1 phosphorylation, iNOS, MHC II and IL-12 production, suggesting negative cross talk between NF-B and STAT1 signalling pathways. Since IKK is required for TNF gene expression and TNF signalling, I investigated the hypothesis that TNF inhibits ‘classical’ macrophage activation through IKK activation. Macrophages from p55-/- and mice treated with anti-TNF antibody show increased STAT1 activation and IL-12 expression after LPS and IFN stimulation. BMDM infected with adenovirus expressing IKKβ dominant negative rescued the inhibitory effect of TNFα on IL-12p40 production, indicating TNFα inhibits IL-12p40 via IKKβ activation. Macrophages are antigen presenting cells while IL-12 and MHC II are critical factors for TH1 cell development. I thus investigate the inhibitory effects of IKKβ∆Mye macrophages in TH1 responses. FACS analysis showed higher MHC II, costimulatory molecules expression on IKKβ∆Mye macrophages after LPS stimulation. In a DTH model, recall assay has shown increased antigen-specific IFN production from IKKMye splenocytes compared to IKKβF/F splenocytes. Furthermore, IFN production was greatly enhanced by CD4+ OTII T cells co-cultured with IKKMye macrophages. Further analysis of CD4+ OTII T cells with qRT-PCR showed increased TH1 genes including IRF1, IFN, IL-12R1 and IL-12R2 and reduced TH2 marker IL-4. In addition to the enhanced antigen-specific T cell responses, IKKMye macrophages also increased anti-tumour immunity. Injection of H-Y positive MB49 tumour cells into IKKF/F and IKKMye female mice has shown tumour rejection, but no tumours were rejected after CD8+ T cells depletion, suggesting tumour rejection is associated with enhanced CTL activity. Taken together, these studies demonstrated the negative regulatory roles of IKK in macrophage activation and their impact to the innate and adaptive immunity.en_US
dc.publisherQueen Mary University of London
dc.titleThe anti-inflammatory role for IkappaB kinase (IKK) beta through inhibition of ‘classical’ macrophage activationen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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    Theses Awarded by Queen Mary University of London

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