DESCRIPTION (provided by applicant): Recognition of the factors associated with maintaining cholesterol balance may illuminate the pathological mechanisms involved in diseases caused by cholesterol excess, with atherosclerosis the leading example. Homeostatic mechanisms that orchestrate cholesterol balance in the vessel wall and defend against atherosclerosis involve reverse cholesterol transport (RCT) from arterial wall to liver. A central mediator of RCT is the enzyme cholesterol 27-hydroxylase (27-OHase). 27-OHase both facilitates cholesterol transport to the liver and, by generating oxysterol signaling molecules, promotes expression of other RCT proteins, specifically ATP binding cassette transporter 1 (ABCA1). Inflammation is an integral feature of atherosclerosis. The autoimmune disorders systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are characterized by high levels of circulating immune reactants and increased risk of atherosclerosis. We have shown that immune reactants affect cellular cholesterol flux by markedly decreasing 27-OHase and ABCA1 expression. We postulate that, in patients with autoimmune disorders, disruption of cholesterol homeostasis by immune reactants leads to accelerated atherosclerosis. To better understand the immunological mechanisms underlying development of atherosclerosis and to begin to counteract the atherogenic consequences, we propose 4 aims: 1) effect of over- and under- expression of 27-OHase on receptors and transport proteins involved in cholesterol flux, with the addition of a pathophysiologic correlate of atherogenesis: quantitation of foam cell transformation of THP-1 macrophages under the various conditions described; 2) immunomodulatory effects of serum from SLE and RA patients on these cholesterol transport/receptor proteins; 3) mechanisms of up regulation of 27-OHase via adenosine receptor agonists and consequent effects on cholesterol trafficking and 4) therapeutic intervention (statins, adenosine agonists) on cholesterol transport/receptor protein gene expression in a murine model (apolipoprotein E knockout mouse).