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J. Biol. Chem., Vol. 276, Issue 49, 45729-45739, December 7, 2001
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From Macrophage-derived foam cells in atherosclerotic
lesions are generally thought to play a major role in the pathology of
the disease. Because macrophages play a central role in the
inflammatory response, and the atherosclerotic lesion has features
associated with chronic inflammatory settings, we investigated foam
cell inflammatory potential. THP-1-derived macrophages were treated with oxidized low density lipoprotein (OxLDL) for 3 days to lipid load
the macrophages and establish a foam cell-like phenotype. The cells
were then activated by treatment with lipopolysaccharide (LPS), and RNA
was harvested at 0, 1, and 6 h after LPS addition. RNA from
treated and control cells was hybridized to microarrays containing
~16,000 human cDNAs. Genes that exhibited a 4-fold or greater
increase or decrease at either 1 or 6 h after LPS treatment were
counted as LPS-responsive genes. Employing these criteria, 127 LPS-responsive genes were identified. Prior treatment of THP-1 macrophages with OxLDL affected the expression of 57 of these 127 genes. Among these 57 genes was a group of chemokine, cytokine, and
signal transduction genes with pronounced expression changes. OxLDL
pretreatment resulted in a significant perturbation of LPS-induced NF
Oxidized Low Density Lipoprotein Exposure Alters the
Transcriptional Response of Macrophages to Inflammatory
Stimulus*
§,, and
CV Therapeutics and ¶ Incyte Genomics, Palo
Alto, California 94304
B activation. Furthermore, some of the OxLDL effects appear to be mediated by the nuclear receptors retinoid X receptor and peroxisomal proliferator-activated receptor 
because pretreatment of
THP-1 macrophages with ligands for these receptors, followed by LPS
treatment, recapitulates the OxLDL plus LPS results for several of the
most significantly modulated genes.
*
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.
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