Noble, Karen Elizabeth; (1999) Monocyte: Endothelium interactions and the control of inflammatory gene expression. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

These studies have focused on the ability of monocytes to influence endothelial cell function in the context of immune and inflammatory responses. Monocytes when cocultured with endothelial cells upregulated E-selectin mRNA and protein expression, with initial appearance on endothelial cells at 3 hours and sustained expression at 21 hours. In contrast, IL-1 induced a transient upregulation. Cell:cell contact was important for monocyte induction of E-selectin expression, an effect which was partially mediated by TNF. Monocyte induction of E-selectin gene expression was NFKB dependent. Addition of exogenous IL-10 to endothelial cell/monocyte cocultures inhibited E-selectin expression at 4 and 21 hours whilst having no effect on E-selectin induction by IL-1 or TNF. In addition, coculture with endothelial cells induced monocyte expression of IL-10 mRNA with maximal levels at 30 hours. Monocytes influenced endothelial cell survival and expression of the bcl-2 homologue, A1, an anti-apoptosis gene. The level of A1 mRNA in serum starved endothelial cells decreased with time, however, addition of monocytes to serum starved endothelial cells increased A1 gene expression for up to 21 hours compared to the transient induction by IL-1. Coculture of monocytes with serum starved endothelial cells reduced endothelial cell death at 21 hours. Cell:cell contact was required for maximal A1 mRNA induction. The role of calcium-dependent proteases in leukocyte transmigration was investigated using calpain inhibitors. Addition of calpain inhibitors reduced the migration of monocytes and neutrophils through cytokine stimulated endothelial monolayers as well as chemokine stimulated migration across unactivated endothelium. Adhesion of leukocytes to the endothelium was not affected by the presence of calpain inhibitors. These studies have demonstrated the ability of peripheral blood monocytes to influence the function and survival of endothelial cells, and have also investigated the molecular mechanisms responsible for such interactions.

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