Is Nicotinic Acid Anti-Inflammatory? Yes, but this does not mean that smoking cigarettes is ok.

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Is Nicotinic Acid Anti-Inflammatory? Yes, but this does not mean that smoking cigarettes is ok.

Anti-Inflammatory Effects of Nicotinic Acid in Human Monocytes Are Mediated by GPR109A Dependent Mechanisms

Originally published, Thrombosis, and Vascular Biology. 2012;32:669–676



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).


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.


In patients with prior myocardial infarction, nicotinic acid (NA) reduces long-term mortality1 and may confer additional antiatherogenic benefits when used in conjunction with statins.2,3 These effects are generally attributed to favorable actions on the lipoprotein profile, which include LDL-cholesterol reduction and HDL-cholesterol elevation.
In addition, NA reduces systemic markers of inflammation (eg, high-sensitivity C-reactive protein, monocyte chemoattractant protein-1 [MCP-1], and TNF-α) and increases adiponectin, an adipokine with insulin sensitizing, antiatherogenic, and anti-inflammatory properties.2,4 These observations raise the possibility of additional nonlipoprotein-mediated effects of NA. The receptor for NA, GPR109A, is abundantly expressed in adipocytes, where it suppresses free fatty acid release5 and has G-protein coupled receptor-mediated anti-inflammatory effects.6 It is also expressed in immune cells including monocytes, macrophages, neutrophils, dendritic cells, and skin Langerhans cells, but a clear role for this receptor in these cells has yet to be elicudated.79 Monocytes and macrophages are key mediators of inflammation; they play a central role in the genesis and pathology of atherosclerosis and represent an important therapeutic target.10 Given the anti-inflammatory effects of NA in adipocytes, the presence of GPR109A in macrophages suggests a potentially more complex macrophage-mediated role for NA in the modulation of atherosclerosis. A recent study using the LDL-receptor−/− mouse model of atherosclerosis showed significant inhibition of disease progression with dietary NA treatment, which was not accompanied by changes in the lipoprotein profile; this effect was not observed in equivalent mice that were GPR109A-deficient.11 Significantly, the effects of NA were also abrogated by bone marrow transplantation from GPR109A-deficient mice into atherosclerosis-prone recipients, suggesting that the observed effects of NA were mediated by bone marrow-derived cells.11 Unknown, however, is whether these and other anti-inflammatory effects of NA pertain in human monocytes and the cellular mechanisms through which this drug may act. In addition, it is not known whether anti-inflammatory effects may be altered by interactions with drugs used in the treatment of the side effects associated with niacin, such as administration of prostaglandin D2 (PGD2) receptor antagonists to counteract flushing. Here, we test the effects of NA on human monocytes and explore its mechanisms of action on a range functions that are relevant to atherogenesis.
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