Low cell cholesterol levels increase NFκB activity through a p38 MAPK-dependent mechanism

Calleros, Laura; Lasa, Marina; Toro, María Josefa Plá del; Chiloeches, Antonio

doi:10.1016/j.cellsig.2006.05.012

Cited by 61 publications

(53 citation statements)

References 66 publications

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“…burgdorferi lysate stimulation of phagocytic cells results in p38␣ MAP kinase-mediated phosphorylation of RelA. We argued that our previous results could be due to a direct effect of p38 MAP kinase on NF-B activation (10,26,36,53) or an indirect effect due to decreased p38 MAP kinase-mediated TNF-␣ production (2), which also activates NF-B (53). In order to dissociate these two alternatives, we first sought to determine whether p38 MAP kinase inhibition during stimulation of macrophages with the spirochete affected the degradation of I-B␣, the inhibitory subunit of the NF-B complex at early time points, in which no TNF-␣ is yet produced (data not shown).…”

Section: Resultsmentioning

confidence: 76%

“…However, the intracellular signaling pathways leading to the expression of proinflammatory cytokines in response to B. burgdorferi remain unsolved. Others have reported previously that p38 MAP kinase signaling is required for NF-B activation in response to different stimuli (10,26,36,53). Furthermore, NF-B has been identified as the transcriptional regulator of TNF-␣ in murine macrophages (1,11,14).…”

Section: Resultsmentioning

confidence: 99%

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p38 Mitogen-Activated Protein Kinase Controls NF-κB Transcriptional Activation and Tumor Necrosis Factor Alpha Production through RelA Phosphorylation Mediated by Mitogen- and Stress-Activated Protein Kinase 1 in Response toBorrelia burgdorferiAntigens

et al. 2007

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The interaction of Borrelia burgdorferi, the causative agent of Lyme borreliosis, with phagocytic cells induces the activation of NF-B and the expression of proinflammatory cytokines including tumor necrosis factor alpha (TNF-␣). B. burgdorferi-induced TNF-␣ production is also dependent on the activation of p38 mitogenactivated protein (MAP) kinase. The specific contribution of these signaling pathways to the response of phagocytic cells to the spirochete and the molecular mechanisms underlying this response remain unresolved. We now show that p38 MAP kinase activity regulates the transcriptional activation of NF-B in response to spirochetal lysate stimulation of phagocytic cells. The regulation occurs at the nuclear level and is independent of the translocation of the transcription factor to the nucleus or its capacity to bind to specific DNA target sequences. In RAW264.

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

p38 Mitogen-Activated Protein Kinase Controls NF-κB Transcriptional Activation and Tumor Necrosis Factor Alpha Production through RelA Phosphorylation Mediated by Mitogen- and Stress-Activated Protein Kinase 1 in Response toBorrelia burgdorferiAntigens

et al. 2007

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“…25HC is also a potent inducer of MCP-1, MIP-1␤, and IL-8 secretion in vitro (53,46). 25HC treatment results in a significant increase in NF-B transcriptional activity, not only by affecting IB degradation and the translocation of p65/NF-B to the nucleus, but also by regulating p65/ NF-B transactivation (9). Oxysterols also induce inflammation and oxidation by inducing slight mitochondrial dysfunctions and increasing reactive oxygen species (ROS) (9).…”

Section: Discussionmentioning

confidence: 99%

25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages

Shen²,

Ma³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The nuclear receptor peroxisome proliferator-activated receptors (PPARs) are important in regulating lipid metabolism and inflammatory responses in macrophages. Activation of PPAR␥ represses key inflammatory response gene expressions. Recently, we identified a new cholesterol metabolite, 25-hydroxycholesterol-3-sulfate (25HC3S), as a potent regulatory molecule of lipid metabolism. In this paper, we report the effect of 25HC3S and its precursor 25-hydroxycholesterol (25HC) on PPAR␥ activity and on inflammatory responses. Addition of 25HC3S to human macrophages markedly increased nuclear PPAR␥ and cytosol IB and decreased nuclear NF-B protein levels. PPAR␥ response element reporter gene assays showed that 25HC3S significantly increased luciferase activities. PPAR␥ competitor assay showed that the Ki for 25HC3S was ϳ1 M, similar to those of other known natural ligands. NF-B-dependent promoter reporter gene assays showed that 25HC3S suppressed TNF␣-induced luciferase activities only when cotransfected with pcDNAI-PPAR␥ plasmid. In addition, 25HC3S decreased LPSinduced expression and release of IL-1␤. In the PPAR␥-specific siRNA transfected macrophages or in the presence of PPAR␥-specific antagonist, 25HC3S failed to increase IB and to suppress TNF␣ and IL-1␤ expression. In contrast to 25HC3S, its precursor 25HC, a known liver X receptor ligand, decreased nuclear PPAR␥ and cytosol IB and increased nuclear NF-B protein levels. We conclude that 25HC3S acts in macrophages as a PPAR␥ ligand and suppresses inflammatory responses via the PPAR␥/IB/NF-B signaling pathway.peroxisome proliferator-activated receptor-␥; oxysterols; oxysterol sulfation; cholesterol metabolites; inflammatory response; macrophages; nuclear factor-B signaling pathway MACROPHAGES ARE THE KEY CELLULAR PLAYERS in the pathogenesis of atherosclerosis. In the early stage of atherosclerosis, macrophages in arterial walls accumulate lipids. These lipid-loaded macrophages, termed foam cells, are characteristic of a reversible early cellular phase of atherosclerotic lesions. Progressive lipid accumulation leads to further escalation of inflammatory responses and infiltration of inflammatory cells (26). Through this process, early cellular lesions are transformed to late, fibrous, atherosclerotic plaques. Physiological or pharmacological maneuvers that reduce macrophage lipids and inflammatory responses may be effective in preventing or reversing atherosclerosis.Nuclear receptors are ligand-activated transcription factors that regulate the expression of target genes to affect processes as diverse as reproduction, inflammation, development, and metabolism (17). Nuclear receptor peroxisome proliferatoractivated receptors (PPARs) play major roles in the regulation of lipid metabolism, glucose homeostasis, and inflammatory processes and may be ideal targets for therapeutic management strategies for cardiovascular diseases (4,6,11,16,23,42). PPAR␥ appears particularly important in regulating genes involved in lipid metabolism and inflammation (1,8,20,21). The PPAR␥...

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“…25HC increases NF-B transcriptional activity, by increasing IB␣ degradation and nuclear translocation of p65/NF-B, and by regulating p65/NF-B transactivation. However, the mechanism by which 25HC increases IB␣ degradation is unclear (16). Thus, the role of 25HC in inflammatory responses is complicated.…”

Section: Hc3s Suppresses Inflammatory Responses Via a Ppar␥/ Ib␣ Simentioning

confidence: 99%

Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation

Ning

2014

American Journal of Physiology-Endocrinology and Metabolism

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Ren S, Ning Y. Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation. Am J Physiol Endocrinol Metab 306: E123-E130, 2014. First published December 3, 2013 doi:10.1152/ajpendo.00552.2013.-Intracellular lipid accumulation, inflammatory responses, and subsequent apoptosis are the major pathogenic events of metabolic disorders, including atherosclerosis and nonalcoholic fatty liver diseases. Recently, a novel regulatory oxysterol, 5-cholesten-3b, 25-diol 3-sulfate (25HC3S), has been identified, and hydroxysterol sulfotransferase 2B1b (SULT2B1b) has been elucidated as the key enzyme for its biosynthesis from 25-hydroxycholesterol (25HC) via oxysterol sulfation. The product 25HC3S and the substrate 25HC have been shown to coordinately regulate lipid metabolism, inflammatory responses, and cell proliferation in vitro and in vivo. 25HC3S decreases levels of the nuclear liver oxysterol receptor (LXR) and sterol regulatory element-binding proteins (SREBPs), inhibits SREBP processing, subsequently downregulates key enzymes in lipid biosynthesis, decreases intracellular lipid levels in hepatocytes and THP-1-derived macrophages, prevents apoptosis, and promotes cell proliferation in liver tissues. Furthermore, 25HC3S increases nuclear PPAR␥ and cytosolic IB␣ and decreases nuclear NF-B levels and proinflammatory cytokine expression and secretion when cells are challenged with LPS and TNF␣. In contrast to 25HC3S, 25HC, a known LXR ligand, increases nuclear LXR and decreases nuclear PPARs and cytosol IB␣ levels. In this review, we summarize our recent findings, including the discovery of the regulatory oxysterol sulfate, its biosynthetic pathway, and its functional mechanism. We also propose that oxysterol sulfation functions as a regulatory signaling pathway. oxysterol sulfate; nuclear receptor; cholesterol and triglyceride metabolism;

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Low cell cholesterol levels increase NFκB activity through a p38 MAPK-dependent mechanism

Cited by 61 publications

References 66 publications

p38 Mitogen-Activated Protein Kinase Controls NF-κB Transcriptional Activation and Tumor Necrosis Factor Alpha Production through RelA Phosphorylation Mediated by Mitogen- and Stress-Activated Protein Kinase 1 in Response toBorrelia burgdorferiAntigens

p38 Mitogen-Activated Protein Kinase Controls NF-κB Transcriptional Activation and Tumor Necrosis Factor Alpha Production through RelA Phosphorylation Mediated by Mitogen- and Stress-Activated Protein Kinase 1 in Response toBorrelia burgdorferiAntigens

25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages

Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation

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