Abstract 14830: Anti-inflammatory Effects of Nicotinic Acid: Mechanisms of Action in Human Monocytes
Objectives: Nicotinic acid (NA) treatment is associated with benefits in atherosclerosis that are attributed to effects on plasma lipoproteins. The nicotinic acid receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible role for NA in modulating function of these immune cells. This study sought to test the effects of nicotinic acid on human monocytes and explore its mechanisms of action on a range functions that are relevant to atherogenesis.
Methods and Results: Human monocytes were isolated from blood taken from healthy volunteers according to local ethics protocols and informed consent was obtained. NA reduced secretion of pro-inflammatory mediators in human monocytes. In the cells treated with NA, release of TNF-α was attenuated by 49.2 ± 4.5%; IL-6 by 56.2 ± 2.8% and MCP-1 by 43.2 ± 3.1% (n=7, P < 0.01). Quantitative RT-PCR showed that mRNA for each of these inflammatory mediators was similarly reduced. In contrast, mRNA for PPAR-γ was increased by 80.5 ± 5.3% fold (n=3, P < 0.01). Nicotinic acid acted on the NF-kappa B transcription pathway. Pre-incubation with NA 10-4 M reduced phosphorylated IKKβ by 42 ± 2% (n=3, P < 0.001) and phosphorylated IKB-α by 54 ± 14% (n=3, P < 0.01). Accumulation of nuclear p65 NF-κB in THP-1 monocytes in response to LPS treatment was inhibited, by 89 ± 1.3 % (n=4, P < 0.01), with NA pre-treatment, to below the level detected in non-stimulated cell extracts. Furthermore, NA attenuated TLR2 and TLR4 mediated release of TNF-α by 40 ± 2% (n=3, P < 0.05) and 46% ± 3 % (n=3, P < 0.05) respectively. Nicotinic acid potently inhibited monocyte adhesion to activated HUVEC, mediated by allosteric changes in the integrin, very late antigen-4 (VLA-4). Chemotaxis of human monocytes in response to media taken from activated HUVEC was reduced by 45.7% ± 1.2%; (n=4, P < 0.001).
Conclusions: Nicotinic acid has potent anti-inflammatory effects on human monocytes. These non lipoprotein-dependent modes of action suggest a potential rationale for treatment with NA that is not dependent on levels of plasma cholesterol, and present possible applications beyond the treatment of atherosclerosis and dyslipidemia.
- © 2011 by American Heart Association, Inc.