TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells
Abstract
Recent evidence suggests that tumor necrosis factor α (TNFα) signaling in vascular cells can have antiatherogenic consequences, but the mechanisms are poorly understood. TNFα 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 TNFα induces ABCA1 mRNA and protein in control and cholesterol-loaded macrophages and enhances cholesterol efflux to apolipoprotein A-I. The induction of ABCA1 by TNFα is reduced by 65% in IκB kinase β-deficient macrophages and by 30% in p38α-deficient macrophages, but not in jun kinase 1 (JNK1)- or JNK2-deficient macrophages. To evaluate the potential pathophysiological significance of these observations, we fed TNFα-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 TNFα signaling and by liver X receptor activation. Thus, TNFα signals primarily through NF-κB 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.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- February 2006
- DOI:
- 10.1073/pnas.0510345103
- Bibcode:
- 2006PNAS..103.3112G
- Keywords:
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- BIOLOGICAL SCIENCES / BIOCHEMISTRY