Effect of Œstradiol-17β on Human Peripheral Blood Monocyte Function In Vitro

Œstrogen replacement therapy in post-menopausal women exerts a protective effect against atherosclerosis, but the mechanism of its action is not clear. One of the early events in the development of atherosclerosis, is the adhesion of mononuclear phagocytes to the endothelial cells of the artery. Therefore, it was proposed that the benefits of œstradiol treatment could be by its action on the monocyte. Hence, it was hypothesised that œstradiol affects monocyte functions, which resulted in four investigations reported in this thesis. One of the effects of œstradiol could be by reducing monocyte hydrogen peroxide production. Studies on monocyte hydrogen peroxide production showed that œstradiol activated human peripheral blood monocytes to produce increased amounts of hydrogen peroxide in vitro. These studies also indicated that monocytes could contain multiple types of binding sites for œstradiol, which was confirmed by œstradiol binding studies. The intracellular effect of œstradiol was investigated by studying the de novo protein synthesis patterns, which showed no difference in the band patterns between control cells and œstradiol-17β-treated cells. The final investigation showed that œstradiol does not contribute to any quantitative changes in the surface receptor expression of CD11 a, CD11 b, CD14 and CD18 but down modulates the adherence and phagocytic functions of CD11 b/CD18 receptors in vitro. With the help of these investigations it is possible to propose a new overall hypothesis of œstradiol action on the monocyte. We hypothesise that œstradiol effects monocyte function in at least two ways. First, œstradiol could activate Monocytes to produce increased amounts of hydrogen peroxide following an appropriate stimulation (probably by cytokines) in vivo, thus causing vasorelaxation of blood vessels. Secondly, œstradiol could reduce the adhesion of monocytes to the arterial endothelium by down modulating the functional activity of some adhesion molecules. Both these effects of œstradiol would help in reducing atherosclerosis and Coronary Artery Disease.