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

ABSTRACT: 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.

SUBMITTER: Gerbod-Giannone MC

PROVIDER: S-EPMC1413897 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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

Gerbod-Giannone Marie-Christine MC Li Yankun Y Holleboom Adriaan A Han Seongah S Hsu Li-Chung LC Tabas Ira I Tall Alan R AR

Proceedings of the National Academy of Sciences of the United States of America 20060221 9

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 atheros ...[more]

PMID: 16492740

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Project description:The ability of the transcription factor NF-kappaB to upregulate anti-apoptotic proteins has been linked to the chemoresistance of solid tumors to standard chemotherapy. In contrast, recent studies have proposed that, in response to doxorubicin, NF-kappaB can be pro-apoptotic through repression of anti-apoptotic target genes. However, there is little evidence analyzing the outcome of NF-kappaB inhibition on the cytotoxicity of doxorubicin in studies describing pro-apoptotic NF-kappaB activity. In this study, we further characterize the activation of NF-kappaB in response to doxorubicin and evaluate its role in chemotherapy-induced cell death in sarcoma cells where NF-kappaB is reported to be pro-apoptotic. Doxorubicin treatment in U2OS cells induced canonical NF-kappaB activity as evidenced by increased nuclear accumulation of phosphorylated p65 at serine 536 and increased DNA-binding activity. Co-treatment with a small molecule IKKbeta inhibitor, Compound A, abrogated this response. RT-PCR evaluation of anti-apoptotic gene expression revealed that doxorubicin-induced transcription of cIAP2 was inhibited by Compound A, while doxorubicin-induced repression of other anti-apoptotic genes was unaffected by Compound A or siRNA to p65. Furthermore, the combination of doxorubicin and canonical NF-kappaB inhibition with Compound A or siRNA to p65 resulted in decreased cell viability measured by trypan blue staining and MTS assay and increased apoptosis measured by cleaved poly (ADP-ribose) polymerase and cleaved caspase 3 when compared to doxorubicin alone. Our results demonstrate that doxorubicin-induced canonical NF-kappaB activity associated with phosphorylated p65 is anti-apoptotic in its function and that doxorubicin-induced repression of anti-apoptotic genes occurs independent of p65. Therefore, combination therapies incorporating NF-kappaB inhibitors together with standard chemotherapies remains a viable method to improve the clinical outcomes in patients with advanced stage malignancies.

Dataset Information

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

Publications

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

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