Oxidized Low Density Lipoprotein Inhibits Interleukin-12 Production in Lipopolysaccharide-activated Mouse Macrophages via Direct Interactions between Peroxisome Proliferator-activated Receptor-γ and Nuclear Factor-κB

Chung, Sung Min; Kang, Bok Yun; Kim, Seung Hyun; Pak, Youngmi Kim; Cho, Daeho; Trinchieri, Giorgio; Kim, Tae Sung

doi:10.1074/jbc.m002577200

Cited by 322 publications

(248 citation statements)

References 61 publications

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“…This is in contrast to the PPARb/RXR heterodimer that constitutively binds to the DNA. 12 Besides transcriptional regulation via direct DNA binding, PPARg attenuates gene expression by scavenging other transcription factors such as NF-kB 13 or by hindering transcriptional cofactors to exert their costimulatory role. These effects are mediated by direct protein-protein interactions.…”

Section: Introductionmentioning

confidence: 99%

Recognition of apoptotic cells by macrophages activates the peroxisome proliferator-activated receptor-γ and attenuates the oxidative burst

et al. 2005

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It is appreciated that phagocytosis of apoptotic cells (AC) is an immunological relevant process that shapes the proversus anti-inflammatory macrophage phenotype. It was our intention to study the respiratory burst, a prototype marker of macrophage activation, under the impact of AC. Following incubation of RAW264.7 macrophages with AC, we noticed attenuated production of reactive oxygen species (ROS) in response to PMA treatment, and observed a correlation between attenuated ROS formation and suppression of protein kinase Ca (PKCa) activation. EMSA analysis demonstrated an immediate activation of peroxisome proliferatoractivated receptor-c (PPARc) following supplementation of AC to macrophages. In macrophages carrying a dominantnegative PPARc mutant, recognition of AC no longer suppressed PKCa activation, and the initial phase of ROS formation was largely restored. Interference with actin polymerization and transwell experiments suggest that recognition of AC by macrophages suffices to attenuate the early phase of ROS formation that is attributed to PPARc activation.

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Section: Introductionmentioning

confidence: 99%

Recognition of apoptotic cells by macrophages activates the peroxisome proliferator-activated receptor-γ and attenuates the oxidative burst

et al. 2005

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“…Oxidized low-density lipoprotein (LDL) can also promote the maturation of DCs from monocyte precursors and causes the down-regulation of interleukin (IL)-12 production in DCs. [11][12][13] DCs are also early participants in developing diabetic lesions before the appearance of scavenger macrophages, 14 and DCs are present in atherosclerotic arteries. 15 To test the hypothesis that DCs may acquire fat and glycogen stores during development, we studied DCs developing from mouse bone marrow stem cells with and without increasing doses of IL-4 or lipopolysaccharide (LPS), both of which promote the stimulatory ability of DCs for T cells.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Developing dendritic cells become ‘lacy’ cells packed with fat and glycogen

Maroof¹,

English²,

Bedford³

et al. 2005

Immunology

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SummaryOn maturation, dendritic cells (DCs) become highly active cells equipped for antigen uptake, migration and clustering and activation of T cells. We therefore asked whether DCs acquire fat and glycogen stores as they mature. DCs were generated from mouse bone marrow stem cells by culturing with granulocyte-macrophage colony-stimulating factor (GM-CSF) for 7-8 days. Stimulation of the DCs with lipopolysaccharide (LPS) for the last 24 hr of culture, or exposure to 1-15 ng/ml of interleukin (IL)-4 during development, resulted in production of DCs not only with an increased ability to stimulate T cells but also with an increasingly lacy appearance on transmission electron microscopy, with multiple unstained areas in the cytoplasm. This changed morphology was associated with the presence of increasing amounts of fat and glycogen, identified by Sudan Black and periodic acid leukofushin/Schiff (PAS) staining, respectively. Lacy DCs up-regulated type 1 and type 2 scavenger receptors, providing possible mechanisms contributing to these changes. Lacy DCs were found occasionally amongst freshly isolated splenic and lymph node DCs. DCs can be isolated from human adipose tissue, and we tested whether lacy DCs acquiring fat and glycogen were present in mouse omentum. CD45 + cells migrating from the omentum expressed specific DC markers CD11c and 33D1, costimulatory molecules and major histocompatibility complex (MHC) class II, and most showed darkly staining fat inclusions. Thus, during development, DCs can acquire large amounts of fat and glycogen, accumulation of which is promoted by antigen exposure and modulated by the cytokine milieu and location, and which may act as a link between energy stores and immune function.

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“…OxLDL has been shown to be a powerful regulator of cell signaling in provoking various responses, among others, expression of adhesion molecules on endothelial cells (5), production of proinflammatory cytokines and growth factors by vascular cells (6), or proliferation and migration of vascular cells (7). In addition, oxLDL is both a potent chemoattractant for circulating monocytes (8) and a differentiating agent that promotes transition of macrophages to lipid-loaded foam cells (9). In close association, receptor-mediated endocytosis of oxLDL by several scavenger receptor family members including macrophage class A scavenger receptor (10,11), CD36 (12), scavenger receptor that binds phosphatidylserine and oxidized lipoprotein (13), or lectin-like oxidized low density lipoprotein receptor-1 (14) is implicated in the process of atherogenesis.…”

mentioning

confidence: 99%

Dualism of Oxidized Lipoproteins in Provoking and Attenuating the Oxidative Burst in Macrophages: Role of Peroxisome Proliferator-Activated Receptor-γ

Fischer

Knethen

Brüne

2002

The Journal of Immunology

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Activation and deactivation of macrophages are of considerable importance during the development of various disease states, atherosclerosis among others. Macrophage activation is achieved by oxidized lipoproteins (oxLDL) and is determined by oxygen radical (ROS) formation. The oxidative burst was measured by flow cytometry and quantitated by oxidation of the redox-sensitive dye dichlorodihydrofluorescein diacetate. Short-time stimulation dose-dependently elicited ROS formation. Diphenylene iodonium prevented ROS formation, thus pointing to the involvement of a NAD(P)H oxidase in producing reduced oxygen species. In contrast, preincubation of macrophages with oxLDL for 16 h showed an attenuated oxidative burst upon a second contact with oxLDL. Taking into account that oxLDL is an established peroxisome proliferator-activated receptor-γ (PPARγ) agonist and considering the anti-inflammatory properties of PPARγ, we went on and showed that a PPARγ agonist such as ciglitazone attenuated ROS formation. Along that line, major lipid peroxidation products of oxLDL, such as 9- and 13-hydroxyoctadecadienoic acid, shared that performance. Supporting evidence that PPARγ activation accounted for reduced ROS generation came from studies in which proliferator-activated receptor response element decoy oligonucleotides, but not a mutated oligonucleotide, supplied in front of oxLDL delivery regained a complete oxidative burst upon cell activation. We conclude that oxLDL not only elicits an oxidative burst upon first contact, but also promotes desensitization of macrophages via activation of PPARγ. Desensitization of macrophages may have important consequences for the behavior of macrophages/foam cells in atherosclerotic lesions.

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Oxidized Low Density Lipoprotein Inhibits Interleukin-12 Production in Lipopolysaccharide-activated Mouse Macrophages via Direct Interactions between Peroxisome Proliferator-activated Receptor-γ and Nuclear Factor-κB

Abstract: Lipopolysaccharide (LPS) increases the production of interleukin-12 (IL-12

Cited by 322 publications

References 61 publications

Recognition of apoptotic cells by macrophages activates the peroxisome proliferator-activated receptor-γ and attenuates the oxidative burst

Recognition of apoptotic cells by macrophages activates the peroxisome proliferator-activated receptor-γ and attenuates the oxidative burst

Developing dendritic cells become ‘lacy’ cells packed with fat and glycogen

Dualism of Oxidized Lipoproteins in Provoking and Attenuating the Oxidative Burst in Macrophages: Role of Peroxisome Proliferator-Activated Receptor-γ

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