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J. Biol. Chem., Vol. 279, Issue 27, 28781-28788, July 2, 2004

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Oxidized Low Density Lipoprotein Blocks Lipopolysaccharide-induced Interferon Synthesis in Human Macrophages by Interfering with IRF3 Activation^*

Angie Marson, Richard M. Lawn, and Thomas Mikita

From the CV Therapeutics, Inc., Palo Alto, California 94304

In response to lipopolysaccharide (LPS) exposure, macrophages activate the transcription of a large number of pro-inflammatory genes by way of signaling pathways downstream of the LPS receptor, Toll-Like Receptor 4. Many of these genes are expressed sequentially in time, with early synthesis events resulting in the secretion of soluble factors that drive the transcription of genes expressed later in the activation cycle. In this study we show that human blood-derived macrophages pretreated with oxidized low density lipoprotein (OxLDL) fail to transcribe and secrete interferon beta (IFN) immediately following LPS stimulation. As such, the normal downstream activation of Stat1 is blocked, and numerous IFN/Stat1-activated genes, including the chemokines IP10 and ITAC, are weakly expressed or not expressed at all in these cells. Inspection of the LPS-induced activation state of several transcription factors known to play a prominent role in IFN transcription reveals that, although NFB, c-Jun, and ATF-2 activation appears normal, the LPS-induced activation of IFN regulatory factor 3 (IRF3), as measured by DNA-binding activity and association with the coactivator CBP, is inhibited in the OxLDL pre-treated cells. These IRF3 activities have been shown to be essential for the initiation of transcription of the IFN gene, and the loss of these activities presumably accounts for the lack of LPS-induced IFN transcription seen in the OxLDL pre-treated cells.

Received for publication, December 3, 2003 , and in revised form, April 14, 2004.

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

To whom correspondence should be addressed: CV Therapeutics, Inc., 3172 Porter Dr., Palo Alto, CA 94304. Tel.: 650-384-8206; Fax: 650-475-0391; E-mail: tom.mikita{at}cvt.com.

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