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Title: Autoregulation of pro-inflammatory protein expression in murine macrophages by nitric oxide
Author: Connelly, Linda
ISNI:       0000 0001 3561 2726
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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Macrophages are effector cells of the immune system that participate in host defence through the killing and removal of bacteria, tumour cells and other pathogenic stimuli. One mechanism of cytotoxicity and cytostasis employed by the activated macrophage is the up-regulation/expression of the enzyme inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO). A key transcription factor activated in response to pathogenic stimuli, including bacterial lipopolysaccharide (LPS), is nuclear factor-kB (NF-KB); this factor is responsible for the up-regulation of numerous pro-inflammatory proteins such as iNOS, cyclo-oxygenase-2 (COX-2) and interleukin-6 (IL-6). The studies described in this thesis investigated the hypothesis that NO can modulate the activation profile of the macrophage, and pro-inflammatory protein expression, via regulation of NF-KB activity. Such a mechanism may represent a feedback pathway by which NO might regulate its own production through effects on iNOS expression. Potential mechanisms underlying regulation of NF-KB activity and pro-inflammatory protein expression by NO were investigated using cells from NOS knockout mice and activators and inhibitors of soluble guanylate cyclase. Herein it is demonstrated that endogenous NO has a biphasic effect on NF-KB activation by which NO can both up- and down-regulate pro-inflammatory protein expression. At low concentrations of NO both LPS-stimulated NF-KB activity and pro-inflammatory protein expression were augmented while at high concentrations NO exerted an inhibitory effect. Thus, NO acts in both a pro- and anti-inflammatory manner depending on the local concentration, initially augmenting macrophage activation and then assisting in the down-regulation of the response. These opposing actions of NO may involve the activity of constitutive and inducible isoforms of NOS in addition to cGMP -dependent and -independent pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry