Abstract
The atheroprotective role of apolipoprotein E (apoE) is well established. During inflammation, expression of apoE in macrophages is reduced leading to enhanced atheromatous plaque development. In the present study, we investigated the signaling pathways involved in the repression of apoE gene expression in response to lipopolysaccharide (LPS) treatment, a condition that mimics the inflammatory stress, in mouse macrophages RAW 264.7. We identified Tpl-2 and MEKK1 as the kinases that are primarily responsible for the down-regulation of apoE promoter activity by LPS. Using a dominant negative form of IkappaB, we established that Tpl-2 and MEKK1 signaling pathways converge to NF-kappaB acting on the apoE core promoter -55/+73. In addition to NF-kappaB activation, LPS also activated c-Jun via its phosphorylation by JNK. The activity of the apoE promoter was repressed by c-Jun, whereas small interference RNA-mediated inhibition of endogenous c-Jun expression reversed the inhibitory effect of Tpl-2 on the apoE promoter. Transfection experiments and DNA binding assays showed that the binding site for c-Jun is in the -55/+73 region of the apoE promoter. Finally, we showed that LPS inhibited apoE gene expression via activation of the Tpl-2/MEK/ERK pathway acting on a different apoE promoter region. In summary, LPS represses apoE gene expression in macrophages via signaling pathways that involve the upstream kinases Tpl-2 and MEKK1, the intermediate mitogen-activated protein kinases ERK and JNK, and the downstream transcription factors AP-1 and NF-kappaB that inhibit the apoE promoter activity via distinct regions.
Highlights
Various plasma lipoprotein classes, including chylomicrons, very low density lipoproteins, and large high density lipoproteins [1]
LPS Induces ApoE Gene Expression in Monocytes and Inhibits we tested the possible engagement of MEKK1 kinase in
ApoE Gene Expression in Macrophages—To determine the LPS-induced intracellular signaling that leads to apolipoprotein E (apoE) gene effect of bacterial LPS on the expression of apoE in monocytes repression in macrophages
Summary
Various plasma lipoprotein classes, including chylomicrons, very low density lipoproteins, and large high density lipoproteins [1]. As a ligand for the low density lipoprotein receptor family, apoE scavenges lipoprotein remnants and mediates clearance of apoE-rich large high density lipoprotein particles from the serum, a significant determinant of the redistribution of cholesterol and triglycerides between the peripheral tissues and the liver. At the level of atheromas, macrophages are the primary providers of apoE This was elegantly demonstrated in transgenic mice expressing apoE only in macrophages, which were protected from atherosclerosis, even though the plasma levels of apoE were exceedingly low and the animals were hypercholesterolemic [4]. The prominent role of inflammation in atherosclerosis [11] requires further elucidation of the molecular mechanisms at the level of the atherosclerotic plaque, which may lead to novel or more complex anti-inflammatory therapeutic targets. The mechanism involves Toll-like receptor-4-mediated activation of the upstream kinases Tpl-2 and MEKK1, activation and nuclear translocation of the NF-B, and AP-1 transcription factors that act directly on the apoE promoter
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