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1.
AIDS Res Hum Retroviruses ; 20(11): 1210-22, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15588343

ABSTRACT

Macrophages represent one of the primary targets of HIV-1 infection. Changes in gene expression in primary human monocyte-derived macrophages following virus exposure were assessed using oligonucleotide arrays. Over a third of the 100 most modulated genes belonged to the interferon system. Upregulated interferon-stimulated genes included those essential for the innate immune response and also those involved in interferon and virus signal transduction from the cell surface. The promoter regions of a cluster of highly upregulated interferon-stimulated genes were analyzed for common regulatory elements. The nuclear factor in activated T cells (NFAT) and members of the interferon family of transcription factors appeared to be responsible for the upregulation of this set of interferon-stimulated genes following HIV-1 exposure.


Subject(s)
HIV-1/pathogenicity , Interferons/metabolism , Macrophages/virology , Oligonucleotide Array Sequence Analysis , Proteins/metabolism , Up-Regulation , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Profiling , HIV Infections/virology , Humans , Interferons/genetics , Interferons/pharmacology , Macrophage Activation , Macrophages/immunology , Monocytes/immunology , Monocytes/virology , NFATC Transcription Factors , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Proteins/genetics , Transcription Factors/genetics , Transcription Factors/metabolism
2.
J Clin Invest ; 114(11): 1564-76, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15578089

ABSTRACT

PPARalpha, beta/delta, and gamma regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor-ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARalpha, beta, and gamma agonists on foam-cell formation and atherosclerosis in male LDL receptor-deficient (LDLR(-/-)) mice. Like the PPARgamma agonist, a PPARalpha-specific agonist strongly inhibited atherosclerosis, whereas a PPARbeta-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARalpha and PPARgamma agonists, but not the PPARbeta agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARalpha and PPARgamma agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARalpha required LXRs, activation of PPARgamma reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.


Subject(s)
Arteriosclerosis/metabolism , Foam Cells/physiology , PPAR alpha/metabolism , PPAR delta/metabolism , PPAR gamma/metabolism , PPAR-beta/metabolism , Animals , Aorta/cytology , Aorta/metabolism , Aorta/pathology , Arteriosclerosis/pathology , Cholesterol/metabolism , Cholesterol, Dietary , DNA-Binding Proteins , Gene Expression Regulation , Humans , Liver X Receptors , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/metabolism , Male , Mice , Mice, Inbred Strains , Mice, Knockout , Orphan Nuclear Receptors , PPAR alpha/agonists , PPAR alpha/genetics , PPAR delta/agonists , PPAR delta/genetics , PPAR gamma/agonists , PPAR gamma/genetics , PPAR-beta/agonists , PPAR-beta/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Triglycerides/metabolism
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