| Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. | |
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MedLine Citation:
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PMID: 22267479 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. METHODS AND RESULTS: In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-α (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (P<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-α (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (P<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKKβ by 42±2% (P<0.001) IKB-α by 54±14% (P<0.01). Accumulation of nuclear p65 NF-κB in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4; P<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%; P<0.001). CONCLUSION: NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia. |
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Authors:
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Janet E Digby; Fernando Martinez; Andrew Jefferson; Neil Ruparelia; Joshua Chai; Malgorzata Wamil; David R Greaves; Robin P Choudhury |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-01-19 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 32 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-02-20 Completed Date: 2012-04-13 Revised Date: 2012-04-13 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 669-76 Citation Subset: IM |
Affiliation:
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Department of Cardiovascular Medicine, John Radcliffe Hospital, and Sir William Dunn School of Pathology, University of Oxford, Oxford, OX3 9DU, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Inflammatory Agents
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pharmacology* Cell Adhesion / drug effects Cells, Cultured Chemokine CCL2 / metabolism Chemotaxis, Leukocyte / drug effects Cyclooxygenase 2 Inhibitors / pharmacology Human Umbilical Vein Endothelial Cells / drug effects, immunology, metabolism Humans I-kappa B Kinase / metabolism Inflammation / genetics, immunology, metabolism* Inflammation Mediators / metabolism Integrin alpha4beta1 / metabolism Interleukin-6 / metabolism Lipopolysaccharides / pharmacology Monocytes / drug effects*, immunology, metabolism Niacin / pharmacology* Phosphorylation Pyrazines / pharmacology RNA Interference Receptors, G-Protein-Coupled / drug effects*, genetics, metabolism Receptors, Immunologic / antagonists & inhibitors, metabolism Receptors, Nicotinic / drug effects*, genetics, metabolism Receptors, Prostaglandin / antagonists & inhibitors, metabolism Toll-Like Receptor 2 / agonists, metabolism Toll-Like Receptor 4 / agonists, metabolism Transcription Factor RelA / metabolism Transfection Tumor Necrosis Factor-alpha / metabolism Vascular Cell Adhesion Molecule-1 / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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088291//Wellcome Trust; PG/09/076//British Heart Foundation |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents; 0/CCL2 protein, human; 0/Chemokine CCL2; 0/Cyclooxygenase 2 Inhibitors; 0/HCAR2 protein, human; 0/IL6 protein, human; 0/Inflammation Mediators; 0/Integrin alpha4beta1; 0/Interleukin-6; 0/Lipopolysaccharides; 0/Pyrazines; 0/RELA protein, human; 0/Receptors, G-Protein-Coupled; 0/Receptors, Immunologic; 0/Receptors, Nicotinic; 0/Receptors, Prostaglandin; 0/TLR2 protein, human; 0/TLR4 protein, human; 0/Toll-Like Receptor 2; 0/Toll-Like Receptor 4; 0/Transcription Factor RelA; 0/Tumor Necrosis Factor-alpha; 0/Vascular Cell Adhesion Molecule-1; 0/prostaglandin D2 receptor; 51037-30-0/acipimox; 59-67-6/Niacin; EC 2.7.11.10/CHUK protein, human; EC 2.7.11.10/I-kappa B Kinase; EC 2.7.11.10/IKBKB protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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