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

Abstract

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-␣ (by 49.2Ϯ4.5%); interleukin-6 (by 56.2Ϯ2.8%), and monocyte chemoattractant protein-1 (by 43.2Ϯ3.1%) (PϽ0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-␣ (by 48.6Ϯ7.1%), interleukin-6 (by 60.9Ϯ1.6%), and monocyte chemoattractant protein-1 (by 59.3Ϯ5.3%) (PϽ0.01; nϭ7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D 2 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 IKK␤ by 42Ϯ2% (PϽ0.001) IKB-␣ by 54Ϯ14% (PϽ0.01). Accumulation of nuclear p65 NF-B in response to lipopolysaccharide treatment was also profoundly inhibited, by 89Ϯ1.3% (nϭ4; PϽ0.01). 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 45.7Ϯ1.2%; PϽ0.001). 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. (Arterioscler Thromb Vasc Biol. 2012;32:669-676.)Key Words: atherosclerosis Ⅲ cholesterol-lowering drugs Ⅲ macrophages Ⅲ receptors Ⅲ vascular biology I n patients with prior myocardial infarction, nicotinic acid (NA) reduces long-term mortality 1 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-␣) and increases adiponectin, an adipokine with insulin sensitizing, antiatherogenic, and antiinflammatory 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 release 5 and has G-protein coupled rece...

A Biased Non-Gαi OXE-R Antagonist Demonstrates That Gαi Protein Subunit Is Not Directly Involved in Neutrophil, Eosinophil, and Monocyte Activation by 5-Oxo-ETE

“…After removal of nontransmigrated cells using a cotton swab, migrated cells attached to the bottom side of the filter were fixed with 3.7% paraformaldehyde for 30 min at 4˚C. Filters were mounted on microscope slides with DAPI-containing mounting medium, as previously described (19). Migration was analyzed by Zeiss Axiovert 40 CFL microscope and Zeiss A-Plan 103/0.25 Ph1 lens; five images were acquired per filter using a Hamamatsu ORCA-03G digital camera.…”

Pleiotropic effects of niacin: Current possibilities for its clinical use

“…Activation of HCA2 in combination with niacin exerts anti-inflammatory effects in endothelial cells (28), adipocytes (29) and human monocytes (30), which are associated with reduced vascular inflammation and the anti-atheromatous effects of niacin (Fig. 1).…”

“…Furthermore, in adipose tissue, niacin suppresses TNFa-stimulated expression and secretion of proinflammatory cytokines -MCP-1, RANTES and the fractalkines supporting the recruitment of T-lymphocytes and macrophages into atherosclerotic lesions (29). In monocytes, niacin inhibits TLR-4-and TLR-2-induced expression as well as the secretion of TNFa, IL-6, and MCP-1 (30). In rats, high doses of niacin attenuated lung inflammation and improved survival during sepsis while simultaneously down-regulating the NF-κB pathway (47).…”

“…In an in vitro experiment carried out on human umbilical vein endothelial cells (HUVEC) and macrophages, niacin was shown to decrease the secretion of IL-6 and TNFa and was accompanied with the inhibition of NF-kB (p65 and notch1) (48). Guinea pigs were fed a high-fat diet and under niacin administration exhibited downregulated expression of CD36 and NF-κB p65 in the arterial wall (30). The described anti-inflammatory changes were independent of modifications to lipid and eicosanoid concentrations (30).…”

“…Guinea pigs were fed a high-fat diet and under niacin administration exhibited downregulated expression of CD36 and NF-κB p65 in the arterial wall (30). The described anti-inflammatory changes were independent of modifications to lipid and eicosanoid concentrations (30).…”