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M108807200v1
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Papers In Press, published online ahead of print December 10, 2001
J. Biol. Chem, 10.1074/jbc.M108807200
Submitted on September 12, 2001
Revised on November 23, 2001
Accepted on December 10, 2001

Oxysterol activators of liver-X-receptor and 9-cis retinoic acid promote sequential steps in the synthesis and secretion of tumor necrosis factor-a from human monocytes

Mark S. Landis, Hansa V. Patel, and John P. Capone

Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5

Corresponding Author: caponej{at}mcmaster.ca

Liver-X-receptor a (LXRa) is a nuclear hormone receptor that is activated by oxysterols and plays a crucial role in regulating cholesterol and lipid metabolism in liver and cholesterol efflux from lipid-loaded macrophages. Here, we show that treatment of human peripheral blood monocytes or monocytic THP-1 cells with the LXR ligand 22(R)-hydroxycholesterol (22(R)-HC), in combination with 9-cis retinoic acid (9cRA), a ligand for the LXR heterodimerization partner retinoid X receptor (RXR), results in the specific induction of the potent pro-apoptotic and pro-inflammatory cytokine tumor necrosis factor-a (TNF-a). Promoter analysis, inhibitor studies, and order-of-addition experiments demonstrated that TNF-a induction by 22(R)-HC and 9cRA occurs by a novel two-step process. The initial step involves 22(R)-HC-dependent induction of TNF-a mRNA, and intracellular accumulation of TNF-a protein, mediated by binding of LXRa/RXRa to an LXR response element at position -879 of the TNF-a promoter. Subsequent cell release of TNF-a protein occurs via a separable 9cRA-dependent, LXRa-independent step that requires de novo transcription and protein synthesis. Our findings reveal a potentially new dimension to the physiological role of LXRa and identify a unique multi step pathway of TNF-a production that may be of consequence to the normal function of LXR in monocyte/macrophages and in disease conditions such as atherosclerosis.


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