Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms.
Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms.
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DOI：
10.1161/atvbaha.111.241836
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发表时间：
2012-03
期刊：
影响因子：
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通讯作者：
Choudhury RP
中科院分区：
文献类型：
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作者：
Digby JE;Martinez F;Jefferson A;Ruparelia N;Chai J;Wamil M;Greaves DR;Choudhury RP
烟酸（NA）治疗与动脉粥样硬化的益处相关，这通常归因于对血浆脂蛋白的影响。 NA 受体 GPR109A 在单核细胞和巨噬细胞中表达，表明 NA 在调节这些免疫细胞的功能中可能发挥额外作用。我们假设 NA 有可能直接作用于单核细胞，改变炎症介质，从而有助于其体内抗动脉粥样硬化作用。在被Toll样受体（TLR）-4激动剂脂多糖激活的人单核细胞中，NA减少促炎介质的分泌：TNF-α（减少49.2±4.5%）；白细胞介素-6（56.2±2.8%）和单核细胞趋化蛋白-1（43.2±3.1%）（P<0.01）。在 TLR2 激动剂、热灭活的单核细胞增多性李斯特菌激活的人单核细胞中，NA 减少了 TNF-α（减少 48.6±7.1%）、白介素-6（减少 60.9±1.6%）和单核细胞趋化蛋白-1（减少 59.3±5.3%）的分泌（P<0.01；n=7）。 siRNA 敲低 GPR109A 导致 THP-1 单核细胞丧失这种抗炎作用。然而，MK0524 抑制前列腺素 D2 受体或 NS398 抑制 COX2 并不会改变在活化的人单核细胞中观察到的 NA 抗炎作用。 THP-1 单核细胞与 NA 0.1 mmol/L 预孵育可使磷酸化 IKKβ 降低 42±2% (P<0.001)，使 IKB-α 降低 54±14% (P<0.01)。脂多糖处理后核 p65 NF-κB 的积累也受到显着抑制，抑制率达 89±1.3%（n=4；P<0.01）。 NA 有效抑制单核细胞粘附到活化的 HUVEC 和 VCAM（由整合素、极晚期抗原 4 介导）。单核细胞趋化性也显着降低（减少 45.7±1.2%；P<0.001）。 NA 显示出一系列不依赖脂蛋白且具有潜在抗动脉粥样硬化作用。这些作用由 GPR109A 介导，并且独立于前列腺素途径。他们提出了一种不依赖于血浆胆固醇水平的 NA 治疗的基本原理，以及除血脂异常治疗之外的可能应用。
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. 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.