Abstract 5547: Can IL-6 Exert Atheroprotective Action on Human Macrophages via Activation of ABCA1 Through the Jak-2/Stat3 Pathway?
Cholesterol-laden macrophage foam cells constitute a hallmark of the inflammatory dimension of atherosclerosis. The ATP-binding cassette A1 transporter (ABCA1) promotes macrophage cholesterol efflux to apolipoprotein AI (apoAI), thereby attenuating atherosclerotic plaque progression. Interleukin-6 (IL-6) is a macrophage secretory product which may modulate intraplaque inflammation, but whose precise role in atherogenesis is unclear. We therefore evaluated the impact of IL-6 on cholesterol homeostasis in human monocyte-macrophages and THP-1 cells. ABCA1-mediated cholesterol efflux to apoAI was significantly increased (2.5-fold) by IL-6 (50 ng/mL) subsequent to the induction of ABCA1 mRNA and protein levels. Stimulation of ABCA1-mediated cholesterol efflux was however abolished by a specific inhibitor of Jak-2 or the Jak-2/Stat3 signalling pathway. The implication of Stat3 in the stimulatory effect of IL-6 was confirmed by the use of a Stat3 inhibitory peptide. In addition, ABCA1-mediated efflux of cholesterol, driven by the ingestion of apoptotic, free-cholesterol-loaded THP-1 cells, was equally induced by IL-6 in THP-1 phagocytes. Finally, IL-6 enhanced phagocytosis of apoptotic Jurkat cells in THP-1 macrophages, an effect abolished by either a Jak-2 inhibitor or glyburide, an inhibitor of ABCA1 activity. Thus, induction of ABCA1 expression by IL-6 in human monocyte-macrophages through the Jak-2/Stat3 pathway may favour reduction in both foam cell formation and growth of the necrotic plaque core, potentially contributing to enhanced plaque stability.