SUN-224 Testosterone Reduces Expression of Inflammatory Targets in Human Macrophages as a Potential Mechanism to Improve Atherosclerosis

Testosterone reduces expression of inflammatory targets in human macrophages as a potential mechanism to improve atherosclerosis Testosterone deficiency is common in men with type 2 diabetes (T2D) and is associated with greatly elevated risk of cardiovascular mortality. Testosterone replacement therapy (TRT) has beneficial effects on surrogate markers and risk factors of atherosclerosis including inflammation, cholesterol and insulin resistance improving survival in men with T2D. The underlying mechanisms of this action remain poorly understood. Inflammation is a central feature to both T2D and atherosclerosis and is driven by monocyte/macrophages, placing these immune cells at the crossroads of disease pathology. Macrophages are involved in all stages of atherosclerotic plaque development and influence disease progression through the expression of inflammatory cytokines, chemokines and lipid accumulation. The present study investigates the influence of testosterone on inflammatory markers in cultured human macrophages. Human monocyte THP-1 cells and primary monocytes isolated from male, hypogonadal patients with T2D were differentiated into macrophages and treated with testosterone (10-100nM and 10nM respectively) for 24hr. Gene expression of key inflammatory targets IL-1β, IL-6, TNFα, and CCL2 were assessed via qPCR. The effects of testosterone on lipid accumulation and inflammatory targets were further assessed in fatty acid loaded THP-1 cells via oil red O staining and qPCR respectively. Testosterone decreased TNFα, CCL2 and IL-6 expression at 10nM and 50nM in THP1 cells but had no effect on IL-1β. In vitro treatment of primary type 2 diabetic patient monocytes reduced TNFα, IL-1 β and CCL2 compared to control treatments. Lipid loading of THP1 cells demonstrated small non-significant increases in inflammatory targets (IL-1 β, IL-6 and CCL2) at higher fatty acid concentrations. Testosterone reduced lipid accumulation at 30nM but not at other testosterone concentrations and had no effect on inflammatory targets in lipid loaded macrophages. These findings importantly indicate that testosterone influences macrophage inflammatory signals as a potential mechanism to protect against atherosclerotic plaque development in men.