Oxidized low density lipoprotein exposure alters the transcriptional response of macrophages to inflammatory stimulus.
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 approximately 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 kappa B activation. Furthermore, some of the OxLDL effects appear to be mediated by the nuclear receptors retinoid X receptor and peroxisomal proliferator-activated receptor gamma 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.
Mikita
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CV Therapeutics, Palo Alto, California 94304, USA. tomm@cvt.com
Porter
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Lawn
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Shiffman
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D001483:Base Sequence; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D008077:Lipoproteins, LDL / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C099252:oxidized low density lipoprotein; D002784:Cholesterol