|Corcoran, Michael -|
|Meydani, Mohsen -|
|Lichtenstein, Alice -|
|Schaefer, Ernst -|
|Dillard Hirschel, Alice -|
|Lamon-Fava, Stefania -|
Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 18, 2010
Publication Date: August 1, 2010
Citation: Corcoran, M.P., Meydani, M., Lichtenstein, A.H., Schaefer, E.J., Dillard Hirschel, A., Lamon-Fava, S. 2010. Sex hormone modulation of proinflammatory cytokine and CRP expression in macrophages from older men and postmenopausal women. Journal of Endocrinology. 206(2):217-224. Interpretive Summary: Heart disease is caused by the formation of plaques in the coronary arteries, which supply the heart muscle with oxygenated blood. The most important cell in plaques is the macrophage, which is involved both in the accumulation of cholesterol and in the local inflammatory reaction that accompanies the plaque formation. It has long been known that women tend to develop heart disease on average 10 year later than men, and thus it is thought that the female sex hormone estrogen and the male sex hormone testosterone may modulate the function of macrophages. In our study, macrophages obtained from 10 healthy older men and 10 postmenopausal women were cultured in vitro in the presence of estrogen or testosterone. We found that macrophages grown in the presence of testosterone produced less inflammatory molecules. Estrogen did not affect the production of most inflammatory molecules, but increased the production of C-reactive protein (CRP) by macrophages in women with elevated blood levels of LDL or “bad” cholesterol. These results indicate that testosterone may have some anti-inflammatory effects, while estrogen may increase inflammation in women who are already predisposed to heart disease by having elevated levels of atherogenic LDL. These results support the findings of the large Women’s health Initiative study showing that postmenopausal hormone therapy increases the risk of heart disease in some women.
Technical Abstract: Inflammation plays a central role in the development and progression of coronary heart disease (CHD). The sex hormones estrogen and testosterone have been shown to modify the inflammatory response by influencing cytokine expression in human macrophage cells obtained from younger individuals. The effect of these hormones on the expression of proinflammatory markers in macrophages obtained from a CHD-age relevant population has not been studied. Human monocyte-derived macrophage cells (HMDM) were obtained from healthy normolipidemic men and postmenopausal women (age 50-70 years), and cultured in autologous serum along with both physiological and supraphysiological concentrations of estrogen or testosterone. HMDM were stimulated with oxidized low density lipoproteins (oxLDL) and the expression of the cytokines TNF-a, IL-6, and IL-1 beta, and of the acute-phase protein CRP was measured. Both physiological and supraphysiological concentrations of testosterone reduced the expression and secretion of TNF-a and reduced the expression of IL-1 beta, but did not affect IL-6 or CRP expression. Estrogen did not modify the expression of TNF-a, IL-6, and IL-1 beta. Estrogen caused a variable response in CRP expression that was positively associated with the donor’s plasma small dense LDL cholesterol concentration. There were no gender differences in any of the observed effects. Our results indicate that testosterone may exert anti-inflammatory effects by reducing macrophage TNF-a expression while the effects of estrogen on macrophage CRP expression may depend upon the extracellular lipid environment.