Molecular link between cholesterol, cytokines and atherosclerosis.

Current investigation on the origin of atherosclerosis has initiated an intense debate over whether atherosclerosis results from hypercholesterolemia or an inappropriate immune response to vascular injury. Although the role of the immune system has been questioned, the overwhelming body of evidence clearly indicates that atherogenesis is initiated by the interplay between cholesterol and cellular secretion of cytokines (especially IL-6) and apolipoprotein 'E' within the arterial wall. Recent studies have revealed that cells possess two cholesterol-sensors: (a) Receptor-Ck which senses the extracellular cholesterol and initiates signalling pathway responsible for the regulation of genes involved in the cell cycle, cell death, cellular cholesterol homeostasis and cytokines including IL-6; (b) LxR alpha which senses intracellular oxysterols and controls genes involved in cell death, cellular cholesterol homeostasis and cytokine IL-8. These cholesterol sensors define the molecular mechanism responsible for cholesterol-depended regulation of cellular synthesis and secretion of cytokines (IL-6, IL-8) within arterial wall. On the basis of this mechanism, presence of cholesterol and its oxy-derivative in the modified LDL will result in transient activation/deactivation of Receptor-Ck-dependent genes which will give rise to repeated cycles of growth coupled with apoptosis leading to a situation where apoptotic-deficient cells in the arterial wall, would be selected resulting in their accumulation and formation of oligoclonal atherosclerotic plaque.