Up-regulation of the fibrogenic cytokine TGF-β1 by oxysterols:: a mechanistic link between cholesterol and atherosclerosis

Deposition of blood cholesterol in the subendothelial space of major arteries is a main feature of the fibrotic plaque as well as the key event in the progression of atherosclerosis. However, the mechanisms by which cholesterol triggers and sustains the fibrotic degeneration of blood arteries remain undefined. The results reported here indicate that a biologically representative mixture of oxysterols, 27-carbon products of cholesterol oxidation, rather than an individual oxysterol at the same concentration, exerts a strong profibrogenic effect when taken up by macrophages. Incubation of murine and human macrophages with such oxysterol mixture markedly promotes both expression and synthesis of one of the most potent proinflammatory and fibrogenic cytokines, transforming growth factor beta1 (TGF-beta1). By contrast, no effect on TGF-beta1 expression and synthesis was found with unoxidized cholesterol. Macrophage uptake of cholesterol and conversion to foam cells is a hallmark of early atherogenesis, but it appears that cholesterol oxidation products, as well as other low-density lipoprotein oxidation products, are required to generate a proper fibrogenic stimulus that is not fulfilled by cholesterol deposition alone.