TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells

Recent evidence suggests that tumor necrosis factor alpha (TNF alpha) signaling in vascular cells can have antiatherogenic consequences, but the mechanisms are poorly understood. TNFa is released by free cholesterol loaded apoptotic macrophages, and the clearance of these cells by phagocytic macrophages may help to limit plaque development. Macrophage cholesterol uptake induces ATP-binding cassette (ABC) transporter ABCA1 promoting cholesterol efflux to apolipoprotein A-I and reducing atherosclerosis. We show that TNF alpha induces ABCA1 mRNA and protein in control and cholesterol-loaded macrophages and enhances cholesterol efflux to apolipoprotein A-I. The induction of ABCA1 by TNF alpha is reduced by 65% in I kappa B kinase beta-deficient macrophages and by 30% in p38 alpha-adeficient macrophages, but not in jun kinase 1 (JNK1)- or JNK2-deficient macrophages. To evaluate the potential pathophysiological significance of these observations, we fed TNF alpha-secreting free cholesterol-loaded apoptotic macrophages to a healthy macrophage monolayer (phagocytes). ABCA1 mRNA and protein were markedly induced in the phagocytes, a response that was mediated both by TNFa signaling and by liver X receptor activation. Thus, TNF alpha signals primarily through NF-kappa B to induce ABCA1 expression in macrophages. In atherosclerotic plaques, this process may help phagocytic macrophages to efflux excess lipids derived from the ingestion of cholesterol-rich apoptotic corpses.