Tumor Necrosis Factor-α and C-C Motif Chemokine Ligand 18 Associate with Atherosclerotic Lipid Accumulation In situ and In vitro

Atherosclerosis is regarded as a chronic inflammatory disease associated with changes in the innate immune system functioning and cytokine disturbances. Local inflammation in the arterial wall is an important component in the development and growth of atherosclerotic plaques. Inside the lesions, both pro- and anti-inflammatory cytokines were detected, highlighting the complexity of the atherosclerotic process. However, little is known about the expression of these signaling molecules in early human atherosclerotic lesions. In this study, we explored localization of a pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF alpha), and anti-inflammatory chemokine, C-C motif chemokine ligand 18 (CCL18), in the arterial wall of human aorta. We noticed differences in the intensity of staining for TNF alpha and CCL18 in atherosclerotic lesions and grossly normal areas, as well as differences in their localization. While CCL18 prevailed in the areas close to the aortic lumen, TNF alpha was localized in deeper layers of the intima. We next studied the expression of TNF alpha and CCL18 mRNA in lesions corresponding to different stages of atherosclerosis progression and found that it was maximal in lipofibrous plaques that are most enriched in lipids. To test the hypothesis that cytokine expression can be associated with lipid accumulation, we studied the TNF alpha and CCL18 expression profiles in primary human monocyte-derived macrophages after inducing lipid accumulation by incubating cultured cells with atherogenic LDL. We found that intracellular cholesterol accumulation was associated with upregulation of both TNF alpha and CCL18, confirming our hypothesis. These results encourage further investigation of cytokine expression in human atherosclerotic lesions and its role in the atherosclerosis progression.