Obesity Biology Research Unit, Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
PLoS One. 2013 Apr 24;8(4):e61707. doi: 10.1371/journal.pone.0061707. Print 2013.
Increased accumulation of macrophages in adipose tissue in obesity is linked to low-grade chronic inflammation, and associated with features of metabolic syndrome. Vitamin D3 may have immunoregulatory effects and reduce adipose tissue inflammation, although the molecular mechanisms remain to be established. This study investigated the effects of vitamin D3 on macrophage-elicited inflammatory responses in cultured human adipocytes, particularly the signalling pathways involved. Macrophage-conditioned (MC) medium (25% with adipocyte maintenance media) markedly inhibited protein expression of the nuclear factor-κB (NFκB) subunit inhibitor κBα (IκBα) (71%, P<0.001) and increased NFκB p65 (1.5-fold, P = 0.026) compared with controls. Treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) abolished macrophage-induced activation of NFκB signalling by increasing IκBα expression (2.7-fold, P = 0.005) and reducing NFκB p65 phosphorylation (68%; P<0.001). The mitogen-activated protein kinase (MAPK) signalling was activated by MC medium, which was also blunted by 1,25(OH)2D3 with a downregulation of phosphorylated p38 MAPK (32%, P = 0.005) and phosphorylated Erk1/2 (49%, P = 0.001). Furthermore, MC medium (12.5% or 25%) dose-dependently upregulated secretion of key proinflammatory chemokines/cytokines (22-368-fold; all P<0.001) and this was significantly decreased by 1,25(OH)2D3: IL-8 (61% and 31%, P<0.001), MCP-1 (37%, P<0.001 and 36%, P = 0.002), RANTES (78% and 62%, P<0.001) and IL-6 (29%, P<0.001 and 34%, P = 0.019). Monocyte migration-elicited by adipocytes treated with 1,25(OH)2D3 was also reduced (up to 25%, P<0.001). In conclusion, vitamin D3 could be anti-inflammatory in adipose tissue, decreasing macrophage-induced release of chemokines and cytokines by adipocytes and the chemotaxis of monocytes. Our data suggests these effects are mediated by inhibition of the NFκB and MAPK signalling pathways.
肥胖症患者脂肪组织中巨噬细胞的积累增加与低度慢性炎症有关，并与代谢综合征的特征有关。维生素 D3 可能具有免疫调节作用，并减少脂肪组织炎症，尽管其分子机制尚待确定。本研究探讨了维生素 D3 对培养的人脂肪细胞中巨噬细胞引发的炎症反应的影响，特别是涉及的信号通路。与对照组相比，巨噬细胞条件培养基（MC 培养基（含脂肪细胞维持培养基的 25%））显著抑制核因子-κB（NFκB）亚基抑制剂 κBα（IκBα）的蛋白表达（71%，P<0.001），并增加 NFκB p65（1.5 倍，P=0.026）。用 1,25-二羟维生素 D3（1,25(OH)2D3）处理可通过增加 IκBα 表达（2.7 倍，P=0.005）和减少 NFκB p65 磷酸化（68%；P<0.001）来消除巨噬细胞诱导的 NFκB 信号转导的激活。MC 培养基激活丝裂原活化蛋白激酶（MAPK）信号通路，而 1,25(OH)2D3 也可使磷酸化 p38 MAPK（32%，P=0.005）和磷酸化 Erk1/2（49%，P=0.001）下调来减弱其作用。此外，MC 培养基（12.5%或 25%）剂量依赖性地上调关键促炎趋化因子/细胞因子的分泌（22-368 倍；均 P<0.001），1,25(OH)2D3 显著降低了这一分泌：IL-8（61%和 31%，P<0.001）、MCP-1（37%，P<0.001 和 36%，P=0.002）、RANTES（78%和 62%，P<0.001）和 IL-6（29%，P<0.001 和 34%，P=0.019）。用 1,25(OH)2D3 处理的脂肪细胞诱导的单核细胞迁移也减少了（多达 25%，P<0.001）。总之，维生素 D3 可能在脂肪组织中具有抗炎作用，通过脂肪细胞减少巨噬细胞诱导的趋化因子和细胞因子的释放以及单核细胞的趋化性。我们的数据表明，这些作用是通过抑制 NFκB 和 MAPK 信号通路介导的。
