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Title: The effect of flavonoids on inflammatory mediator expression in human monocytic and endothelial cells
Author: Connor, Carol Anne
ISNI:       0000 0004 2672 4656
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2008
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Cardiovascular disease (CVD) is a major cause of mortality in the UK and is likely to rise further due to the increase in obesity and related rise in Type 2 diabetes. In terms of reducing CVD risk, numerous epidemiological and prospective studies have indicated beneficial effects of increased fruit and vegetable consumption. Many polyphenolic compounds, such as quercetin, found in red wine and apples, have also been implicated in protecting against CVD. Hyperglycaemia (elevated blood glucose) is a risk factor for vascular disease in individuals with or without diabetes and it has recently been reported that acute hyperglycaemia is associated with changes in monocyte and endothelial cell function. In this study we examined the effect of hyperglycaemia on inflammatory mediator gene and protein expression in human monocytes and endothelial cells. The initial plan was to look at the effect of quercetin and its metabolites on high glucosestimulated human monocytic and endothelial cells. Glucose did not have a striking effect on inflammatory gene and protein expression in these cells and so we examined the effect of quercetin and its metabolites, and of an apple procyanidin oligomeric compound, on inflammatory-cytokine stimulated umbilical vein endothelial cells. Quercetin, quercetin-3-glucuronide, isorhamnetin-3-glucuronide and the apple procyanidin compound gave a distinct decrease in interleukin (IL)-6 expression in tumour necrosis factor (TNF)-a stimulated cells. IL-6 is an inflammatory cytokine which has been shown to be increased in patients with atherosclerosis and together with its receptor is known to increase adhesion molecule and chemokine expression in endothelial cells. Due to the fact that endothelial cells do not express the receptor for this cytokine we investigated the effect of the flavonoids on cytokine, chemokine and adhesion molecule gene expression in endothelial cells after the addition of soluble IL-6 receptor to the cultures. The inhibitory effect of the flavonoids was more striking after the addition of the receptor compared with cells stimulated with TNF-a alone. We then went on to look at the signalling mechanisms involved, hypothesising that the· flavonoids affect mitogen activated protein (MAP) kinase family activity. Quercetin and quercetin-3-glucuronide decreased c-jun N-terrninal kinase (JNK) phosphorylation. The apple procyanidin compound decreased p38 phosphorylation and increased p44/42 activation. In conclusion, this work shows the beneficial effect of flavonoid compounds on reducing inflammation in endothelial cells. It highlights the importance of interleukin-6 and its receptor in the inflammatory response of these cells and how the flavonoids initial effects on cell signalling can lead to a reduction in mediators involved in atherosclerosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available