Interleukin-18 and Interleukin-12 Together Downregulate ATP-Binding Cassette Transporter A1 Expression Through the Interleukin

therosclerotic cardiovascular disease is one of the major causes of death in developed countries. Lipid accumulation, foam cell formation and inflammation are recognized as major features of atherosclerosis.1 Inflammatory cells, mainly macrophages and T cells, produce a wide range of inflammatory cytokines in atherosclerotic lesions, which contributes significantly to the progress of the disease.2 Interleukin (IL)-18, a member of the IL-1 cytokine family, was described originally as an interferon (IFN)-γ-inducing factor. IL-18 is expressed in human carotid atherosclerotic plaques and has been suggested to be a pro-atherogenic cytokine and to influence plaque instability.3 Like IL-18, IL-12 is a crucial pro-inflammatory cytokine and acts as a pro-atherogenic factor,4 although the primary structural homologies between the 2 cytokines are very low. Recent reports showed that a combination of IL-18 and IL-12 promptly and synergistically induced IFN-γ production in macrophages and vascular smooth muscle cells.5,6 One of the major protective effects of high-density lipoprotein (HDL) on atherosclerosis is its function in reverse cholesterol transport (RCT), a process by which excess cell cholesterol is picked up by HDL particles and delivered to the liver for final excretion.7 The first and rate-limiting step of RCT is believed to be the efflux of cellular free cholesterol onto acceptors. ATP-binding cassette transporter A1 (ABCA1) plays a critical role in this step by mediating the efflux of cholesA