TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

Lei Lei; Ying Xiong; Jia Chen; Jin-Bo Yang; Yi Wang; Xin-Ying Yang; Catherine C. Y. Chang; Bao-Liang Song; Ta-Yuan Chang; Bo-Liang Li

doi:10.1194/jlr.M800484-JLR200

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

^*State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
^†Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03756

1To whom correspondence should be addressed. e-mail: blli{at}sibs.ac.cn

Abstract

High levels of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are present in atherosclerotic lesions. TNF-α regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF-α may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-α enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-α. Our data demonstrate that TNF-α, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF-α is proatherosclerotic during early phase of lesion development.

Footnotes

This work was supported by grants from the Ministry of Science and Technology of China (No. 2006CB910600, 2009CB919000), the National Natural Science Foundation of China (No. 30571057, 30623002), and Shanghai Science and Technology Committee (No. 07JC14061, 08431900500) (B-L.L., B-L.S., and Y.X.), and by National Institutes of Health Grant HL-60306 to T-Y.C.).
Published, JLR Papers in Press, February 2, 2009.
- ACAT, acyl-coenzyme A:cholesterol acyltransferase
- AP-1, activator protein-1
- ATRA, all-trans retinoic acid
- CE, cholesteryl ester
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GM-CSF, granulocyte-macrophage colony stimulating factor
- IFN-γ, interferon-gamma
- IκBα, inhibitor of NF-κB-alpha
- IL-1β, interleukin-1-beta
- IL-6, interleukin-6
- IL-10, interleukin-10
- LPDS, lipoprotein-deficient serum
- LPS, lipopolysaccharide
- MCP-1, monocyte chemotactic protein-1
- M-CSF, macrophage-colony stimulating factor
- NE, nuclear extract
- NF-κB, nuclear factor-kappa B
- oxLDL, oxidized low density lipoprotein
- PGA1, prostaglandin A₁
- PGJ2, 15-deox-Δ^{12, 14}-prostaglandin J₂
- Sp1, specificity protein 1
- TNFα, tumor necrosis factor-alpha