TNFalpha induces ABCA1 through NF-kappaB in macrophages and in phagocytes ingesting apoptotic cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (9), p.3112
• Main Authors: Gerbod-Giannone, Marie-Christine, Li, Yankun, Holleboom, Adriaan, Han, Seongah, Hsu, Li-Chung, Tabas, Ira, Tall, Alan R
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - immunology; Antibodies - pharmacology; Apoptosis - drug effects; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biochemistry; Biology; Blood vessels; Cells; Cells, Cultured; Cholesterol; Cholesterol - pharmacology; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation - drug effects; Liver X Receptors; Macrophages - cytology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; Orphan Nuclear Receptors; Phagocytes - cytology; Phagocytes - drug effects; Phagocytes - immunology; Phagocytes - metabolism; Proteins; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - genetics; Signal transduction; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0027-8424; 1091-6490

Recent evidence suggests that tumor necrosis factor alpha (TNFalpha) signaling in vascular cells can have antiatherogenic consequences, but the mechanisms are poorly understood. TNFalpha 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 TNFalpha induces ABCA1 mRNA and protein in control and cholesterol-loaded macrophages and enhances cholesterol efflux to apolipoprotein A-I. The induction of ABCA1 by TNFalpha is reduced by 65% in IkappaB kinase beta-deficient macrophages and by 30% in p38alpha-deficient macrophages, but not in jun kinase 1 (JNK1)- or JNK2-deficient macrophages. To evaluate the potential pathophysiological significance of these observations, we fed TNFalpha-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 TNFalpha signaling and by liver X receptor activation. Thus, TNFalpha signals primarily through NF-kappaB 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.