Granulocyte-macrophage colony-stimulating factor
positive regulation of macrophage derived foam cell differentiation
Interleukin-1beta and tumour necrosis factor-alpha impede neutral lipid turnover in macrophage-derived foam cells.
<h4>Background</h4>Pro-inflammatory cytokines can affect intracellular lipid metabolism. A variety of effects have been described for different cell types; hepatocyte lipid turnover pathways are inhibited during inflammation, whereas interleukin-1beta (IL-1beta) reduces intracellular cholesterol levels in fibroblasts. Levels of the pro-inflammatory cytokines IL-1beta and tumour necrosis factor-alpha (TNF-alpha) are up-regulated at sites of formation of atherosclerotic plaques. Plaque formation is though to begin with infiltration of monocytes to the intimal layer of the vascular wall, followed by differentiation to macrophages and macrophage uptake of modified lipoproteins, resulting in accumulation of intracellular lipids. The lipid-filled cells are referred to as macrophage foam cells, a key feature of atherosclerotic plaques. We have investigated the effects of IL-1beta and TNF-alpha on macrophage foam cells in order to assess whether presence of the pro-inflammatory cytokines improves or aggravates macrophage foam cell formation by affecting lipid accumulation and lipid turn-over in the cells.<h4>Results</h4>Differentiated primary human macrophages or THP-1 cells were lipid loaded by uptake of aggregated low density lipoproteins (AgLDL) or very low density lipoproteins (VLDL), and then incubated with IL-1beta (0 - 5000 pg/ml) in lipoprotein-free media for 24 h. Cells incubated in absence of cytokine utilized accumulated neutral lipids, in particular triglycerides. Addition of exogenous IL-1beta resulted in a dose-dependent retention of intracellular cholesterol and triglycerides. Exchanging IL-1beta with TNF-alpha gave a similar response. Analysis of fatty acid efflux and intracellular fatty acid activation revealed a pattern of decreased lipid utilization in cytokine-stimulated cells.<h4>Conclusion</h4>IL-1beta and TNF-alpha enhance macrophage foam cell formation, in part by inhibition of macrophage intracellular lipid catabolism. If present in vivo, these mechanisms will further augment the pro-atherogenic properties of the two cytokines.