2Division of Nephrology, 330 Brookline Ave., E/RN 304, Boston, MA 02215, USA.
FASEB J. 2013 Nov;27(11):4366-74. doi: 10.1096/fj.12-223933. Epub 2013 Jul 23.
We investigated the novel role of HCA2 (GPR109A) and its ligand nicotinic acid in regulating macrophage function. Hca2 expression in the RAW264.7 murine macrophage cell line is strongly induced by LPS treatment and correlates with the expression of TNF-α. Treatment with 300 μM nicotinic acid (reported EC50 3 μM, peak plasma concentration 50-300 μM), significantly inhibited TNF-α, IL-6, IL-12p40, and IL-1β production (P<0.05) in LPS (1 ng/ml)-stimulated wild-type murine bone marrow-derived macrophages (BMMs) but failed to do so in Hca2(-/-) BMMs. Treatment with nicotinic acid reduced nuclear factor κB (NF-κB) activation levels by 43% (P<0.03) in wild-type BMMs 6 h after LPS stimulation but not in Hca2(-/-) BMMs. Nicotinic acid significantly inhibited wild-type BMM chemotaxis (P<0.001), but had no effect on the chemotaxis of Hca2(-/-) BMMs. A significant increase in low-density lipoprotein uptake by both wild-type (P<0.006) and Hca2(-/-) BMMs (P<0.03) in response to LPS was observed, which was significantly suppressed by nicotinic acid in wild-type BMMs (P<0.04) but not in Hca2(-/-) BMMs. Our results suggest that the nicotinic acid-HCA2 axis is a novel negative regulator of macrophage activation.
我们研究了 HCA2（GPR109A）及其配体烟酸在调节巨噬细胞功能方面的新作用。LPS 处理强烈诱导 RAW264.7 鼠巨噬细胞系中的 Hca2 表达，并且与 TNF-α 的表达相关。用 300μM 烟酸（报道的 EC50 为 3μM，峰值血浆浓度为 50-300μM）处理可显著抑制 LPS（1ng/ml）刺激的野生型鼠骨髓来源巨噬细胞（BMMs）中 TNF-α、IL-6、IL-12p40 和 IL-1β的产生（P<0.05），但在 Hca2（-/-）BMMs 中则不然。烟酸处理可使 LPS 刺激后 6 小时的野生型 BMMs 中核因子 κB（NF-κB）激活水平降低 43%（P<0.03），但在 Hca2（-/-）BMMs 中则不然。烟酸可显著抑制野生型 BMM 趋化作用（P<0.001），但对 Hca2（-/-）BMMs 的趋化作用则无影响。在 LPS 刺激下，两种 BMMs（野生型，P<0.006；Hca2（-/-），P<0.03）的低密度脂蛋白摄取均显著增加，烟酸可显著抑制野生型 BMMs（P<0.04）但不能抑制 Hca2（-/-）BMMs 的摄取。我们的结果表明，烟酸-HCA2 轴是巨噬细胞活化的一种新的负调控因子。
