Mediators of monocyte activity in inflammation

The effects of incubation of CRP with human primary and monocytic cell lines were examined using monocytic cytokine expression, adhesion molecule expression and adhesion to endothelial cells and intracellular peroxide formation, as end points. Monocytic intracellular signalling events were investigated after interaction of CRP with specific CRP receptors on monocytes. These initial signalling events were examined for their role in modulating monocyric adhesipn molecule and cytokine expression. Monocyte recruitment and retention in the vasculature is also influenced by oxidative stress. Therefore the effect of 6 weeks of antioxidant intervention in vivo was examined on monocytic adhesion molecule expression, adhesion to endothelial cells ex vivo and on serum CRP concentrations, pre- and post- supplementation with the antioxidants vitamin C and vitamin E. In summary, CRP is able to bind Fc?RIIa. CRP binding Fc?R initiates an intracellular signalling cascade that phosphorylates the non-receptor ryrosine kinase, Syk, associated with intracellular ryrosine activating motifs on the cytoplasmic tail of Fey receptors. CRP incubations increased phosphatidyl inositol turnover and Syk phosphorylation ultimately led to Ca2+ mobilisation in monocytes. CRP mediated Syk phosphorylation in monocytes leads to an increase in CD1 lb and IL-6 expression. CRP engagement with monocytes also leads to an increase in peroxide production, which can be inhibited in vitro using the antioxidants a-tocopherol and ascorbic acid. CRP mediated CDllb expression is not redox regulated by CRP mediated changes in cytosolic peroxides. The Fc?RIIa polymorphism at codon 131 effects the phenotypic driven changes described in monocytes by CRP, where R/R allotypes have a greater increase in CD1 lb, in response to CRP, which may be involved in promoting the monocytic inflammatory response. CRP leads to an increase in the expression of pro-inflammatory cytokines, which alters the immune phenotype of circulating monocytes. Vitamin C supplementation reduced monocytic adhesion to endothelial cells, but had no effect on serum levels of CRP.EThOS - Electronic Theses Online ServiceGBUnited Kingdo