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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.

Original publication

DOI

10.1161/ATVBAHA.111.241836

Type

Journal article

Journal

Arterioscler Thromb Vasc Biol

Publication Date

03/2012

Volume

32

Pages

669 - 676

Keywords

Anti-Inflammatory Agents, Cell Adhesion, Cells, Cultured, Chemokine CCL2, Chemotaxis, Leukocyte, Cyclooxygenase 2 Inhibitors, Human Umbilical Vein Endothelial Cells, Humans, I-kappa B Kinase, Inflammation, Inflammation Mediators, Integrin alpha4beta1, Interleukin-6, Lipopolysaccharides, Monocytes, Niacin, Phosphorylation, Pyrazines, RNA Interference, Receptors, G-Protein-Coupled, Receptors, Immunologic, Receptors, Nicotinic, Receptors, Prostaglandin, Toll-Like Receptor 2, Toll-Like Receptor 4, Transcription Factor RelA, Transfection, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1