Tumor necrosis factor-α and C-C motif chemokine ligand 18 associate with atherosclerotic lipid accumulation in situ and in vitro.

Disorders of the innate immune system and associated cytokine disturbances play an important role in atherosclerosis. Although both pro- and anti-inflammatory cytokines have been detected in human atherosclerotic lesions, quantitative data on their expression in early atherosclerotic lesions remains to be reported. We studied localization of a pro-inflammatory cytokine, tumor necrosis factor-α (TNFα), and anti-inflammatory chemokine, C-C motif chemokine ligand 18 (CCL18), in human aorta. The intensity of staining for TNFα and CCL18 in atherosclerotic lesions was higher than in uninvolved tissues. CCL18 prevailed in the intimal layer close to the lumen. TNFα was localized in the deeper layers of the intima. The expression of mRNA of TNFα and CCL18 was maximal in lipofibrous plaques that contain the highest amounts of fat in comparison with other types of atherosclerotic lesions. To test whether cytokine expression is affected by lipid accumulation, we induced cholesterol accumulation in primary human monocyte-derived macrophages by incubating with atherogenic LDL. Accumulation of intracellular cholesterol was accompanied by upregulation of TNFα and CCL18, confirming the hypothesis that pro- and anti-inflammatory responses in arterial wall cells can be influenced by lipid accumulation.