Oxidized cholesterol in oxidized low density lipoprotein may be responsible for the inhibition of LPS-induced nitric oxide production in macrophages1The project was supported by National Natural Science Foundation of China.1

Liu, Shang Xi; Yuan, Cheng; Wan, Jennifer Man-Fan

doi:10.1016/s0021-9150(97)00185-8

Cited by 20 publications

(13 citation statements)

References 38 publications

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“…Although the maximal effect on cytokine release was less than a glucocorticoid receptor agonist, dexamethasone, it would appear that the results obtained here parallel previously published in vitro data. For example, in mouse macrophages, LXR ligands have been shown to reduce LPS-, IL-1␤-, or TNF␣-induced metalloproteinase-9, but not metalloproteinase 12 (MMP-12) and MMP-13, expression at the gene level (17), LPS or bacterial infection induced gene transcription such as iNOS, cyclooxygenase-2, and IL-6 (10), LPS induced NO production (12), and LPS and polyriboinocinic:polyribocytidylic acid induced inflammatory cytokines (13). Similarly, in human blood monocyte-derived macrophages LXR agonists have been shown to inhibit TNF␣ and IL-1␤ expression at the mRNA and protein level (14,16).…”

Section: Discussionmentioning

confidence: 99%

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Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses

Birrell

Catley

Hardaker

et al. 2007

Journal of Biological Chemistry

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The liver X receptors (LXR␣/␤) are part of the nuclear receptor family and are believed to regulate cholesterol and lipid homeostasis. It has also been suggested that LXR agonists possess anti-inflammatory properties. The aim of this work was to determine the effect of LXR agonists on the innate immune response in human primary lung macrophages and a pre-clinical rodent model of lung inflammation. Before profiling the impact of the agonist, we established that both the human macrophages and the rodent lungs expressed LXR␣/␤. We then used two structurally distinct LXR agonists to demonstrate that activation of this transcription factor reduces cytokine production in THP-1 cells and lung macrophages. Then, using the expression profile of ATP binding cassettes A1 (ABCA-1; a gene directly linked to LXR activation) as a biomarker for lung exposure of the compound, we demonstrated an LXR-dependent reduction in lung neutrophilia rodents in vivo. This inhibition was not associated with a suppression of c-Fos/c-Jun mRNA expression or NF-B/AP-1 DNA binding, suggesting that any anti-inflammatory activity of LXR agonists is not via inhibition of NF-B/AP-1 transcriptional activity. These data do not completely rule out an impact of these agonists on these two prominent transcription factors. In summary, this study is the first to demonstrate anti-inflammatory actions of LXRs in the lung. Chronic innate inflammatory responses observed in some airway diseases is thought to be central to disease pathogenesis. Therefore, data suggest that LXR ligands have utility in the treatment of lung diseases that involves chronic inflammation mediated by macrophages and neutrophils.The liver X receptors (LXR) 2 are part of the nuclear receptor super family and exist in two forms known as LXR␣ and LXR␤. These receptors are coded by two separate genes, Nr1h3 and Nr1h2, respectively (1). LXRs form obligate heterodimers with another orphan nuclear receptor, RXR, and regulate cholesterol and lipid homeostasis. Originally it was believed that LXRs were orphan receptors until the discovery of endogenous ligands; that is, the oxysterols (1-4). LXR directly controls the transcription of several genes involved in the cholesterol efflux pathway including ATP binding cassettes A1 (ABCA-1) and G1 (5-8). The nuclear receptors LXR␣ and LXR␤ have been implicated in the control of cholesterol and fatty acid metabolism, and in the intestine ligand activation of LXR/RXR heterodimers dramatically reduces dietary cholesterol absorption, an effect postulated to be mediated by ABCA1 (6). A dual LXR␣/␤ agonist has been shown to reduce the development of atherosclerosis (9), and in a similar murine model the same authors found that two LXR␣/␤ agonists reduced inflammatory mRNA expression. This data suggest that LXR agonists may reduce atherosclerosis not only by promoting cholesterol efflux but also by limiting the production of inflammatory mediators in the artery wall (10). This anti-inflammatory profile has also been shown in two murine models of contact dermati...

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Section: Discussionmentioning

confidence: 99%

“…nitric oxide (10,12), inflammatory cytokines (10,(13)(14)(15)(16), and matrix metalloproteinase 9 (17). Therefore, there is a clear rationale for evaluating the ability of LXR ligands to evoke antiinflammatory activity in the lung (18 -20).…”

mentioning

confidence: 99%

Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses

Birrell

Catley

Hardaker

et al. 2007

Journal of Biological Chemistry

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“…The LDL was oxidized by incubating 200 g/ml of LDL in PBS containing 5 mol/l CuSO4 at 37°C for 27 h (33). This procedure resulted in an electrophoretic mobility for oxidized LDL of 1.0 relative to albumin and 4.0 relative to native LDL (31). Fluorescent labeling of LDL was accomplished by adding 75 l of 3 mg/ml DiI in DMSO to 4 mg of oxidized LDL (33).…”

Section: Methodsmentioning

confidence: 99%

“…Impaired endothelium-dependent vasorelaxation precedes the development of clinical manifestations of the disease and is detectable even before angiographic manifestations become apparent (2,9,14,20,36). One of the mechanisms leading to endothelial dysfunction is the accumulation of an endogenous inhibitor of eNOS, asymmetric dimethylarginine (ADMA) (1,8,13,31,43,46). Plasma levels of ADMA are elevated in patients with chronic renal failure (11,21,22,32,34,44,49), hypercholesterolemia (8, 9, 29, 47), occlusive vascular disease, and hypertension (1, 5, 14, 16 -18, 20, 42, 43, 48) and associated with reduced NO production and impaired endotheliumdependent vasodilation.…”

mentioning

confidence: 99%

Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency

Smirnova¹,

Sawamura²,

Goligorsky³

2004

American Journal of Physiology-Renal Physiology

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Smirnova, I. V., T. Sawamura, and M. S. Goligorsky. Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency. Am J Physiol Renal Physiol 287: F25-F32, 2004. First published March 9, 2004 10.1152/ajprenal.00449.2003.-Endothelial cell dysfunction (ECD) is emerging as a common denominator for diverse cardiovascular abnormalities associated with inhibition of endothelial nitric oxide (NO) synthase (eNOS). Elevated levels of asymmetric dimethylarginine (ADMA), a potent eNOS inhibitor, are common in renal failure and may contribute to ECD. Through DNA microarray screening of genes modulated in human umbilical vein endothelial cells (HUVEC) by N G -nitro-L-arginine methyl ester (L-NAME), we found a 1.8-fold increase in low-density lipoprotein receptor-1 (LOX-1) expression. LOX-1 is a major endothelial receptor for oxidized low-density lipoproteins (OxLDL) and is assumed to play a role in the initiation and progression of atherosclerosis. Here, we confirmed the upregulation of LOX-1 mRNA and protein level by quantitative RT-PCR and Western blot analysis. Increased expression of LOX-1 was associated with the accumulation of DiI-labeled OxLDL (DiI-OxLDL) in ADMA-and L-NAME-pretreated HUVEC. To evaluate the contribution of LOX-1 in ADMA-induced accumulation of OxLDL by HUVEC, we used the competitive receptor inhibitor, soluble LOX-1. Treatment of HUVEC with soluble LOX-1 was associated with an approximately two-to threefold inhibition of DiI-OxLDL uptake in L-NAME-or ADMA-treated HUVEC. In conclusion, ADMA-or L-NAME-induced NO deficiency leads to the increased expression of LOX-1 mRNA and protein in HUVEC, which in turn results in the accumulation of OxLDL. Competition with LOX-1-soluble extracellular domain reduces OxLDL accumulation. In summary, elevated ADMA levels, i.e., in patients with renal failure, may be responsible for endothelial accumulation of OxLDL via upregulated LOX-1 receptor, thus contributing to endothelial lipidosis and dysfunction. asymmetric dimethylarginine; endothelial dysfunction; chronic renal failure ENDOTHELIAL DYSFUNCTION IS emerging as a common denominator for diverse cardiovascular abnormalities, such as atherosclerosis, diabetes, hypertension, and renal failure. Inhibition of endothelial nitric oxide (NO) synthase (eNOS) is one of the hallmarks of developing endothelial cell dysfunction (2, 9, 15, 37). Impaired endothelium-dependent vasorelaxation precedes the development of clinical manifestations of the disease and is detectable even before angiographic manifestations become apparent (2,9,14,20,36). One of the mechanisms leading to endothelial dysfunction is the accumulation of an endogenous inhibitor of eNOS, asymmetric dimethylarginine (ADMA) (1,8,13,31,43,46). Plasma levels of ADMA are elevated in patients with chronic renal failure (11,21,22,32,34,44,49), hypercholesterolemia (8, 9, 29, 47), occlusive vascular disease, and hypertension (1, 5, 14, 16 -18, 20, 42, 43, 48) and associated with reduced NO production an...

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“…However, in certain conditions, anti-oxidative effects of oxysterols have also been described. Thus, oxidized cholesterol in oxLDL may be responsible for the inhibition of lipopolysaccharide (LPS)-induced nitric oxide production in J774-A1 murine macrophages (49).…”

Section: Oxysterols: Potent Pro-oxidative Moleculesmentioning

confidence: 99%

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

Véjux

Malvitte

Lizard³

2008

Braz J Med Biol Res

149

132

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Oxidized cholesterol in oxidized low density lipoprotein may be responsible for the inhibition of LPS-induced nitric oxide production in macrophages1The project was supported by National Natural Science Foundation of China.1

Cited by 20 publications

References 38 publications

Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses

Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses

Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

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