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Originally published In Press as doi:10.1074/jbc.M108807200 on December 10, 2001

J. Biol. Chem., Vol. 277, Issue 7, 4713-4721, February 15, 2002
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Oxysterol Activators of Liver X Receptor and 9-cis-Retinoic Acid Promote Sequential Steps in the Synthesis and Secretion of Tumor Necrosis Factor-alpha from Human Monocytes*

Mark S. LandisDagger , Hansa V. Patel, and John P. Capone§

From the Department of Biochemistry, Faculty of Health Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

Liver X receptor alpha  (LXRalpha ), 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-alpha (TNF-alpha ). Promoter analysis, inhibitor studies, and order-of-addition experiments demonstrated that TNF-alpha 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-alpha mRNA, and intracellular accumulation of TNF-alpha protein, mediated by binding of LXRalpha /RXRalpha to an LXR response element at position -879 of the TNF-alpha promoter. Subsequent cell release of TNF-alpha protein occurs via a separable 9cRA-dependent, LXRalpha -independent step that requires de novo transcription and protein synthesis. Our findings reveal a potentially new dimension of the physiological role of LXRalpha and identify a unique multistep pathway of TNF-alpha production that may be of consequence to the normal function of LXR in monocyte/macrophages and in disease conditions such as atherosclerosis.

* This work was supported in part by the Canadian Institutes of Health Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Holds an Ontario Graduate Scholarship from the Province of Ontario.

§ To whom correspondence should be addressed: Tel.: 905-525-9140 (ext. 22184); Fax: 905-546-0800; E-mail: caponej@mcmaster.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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