Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-α (TNF-α) expression via ERK1/2 activation and Egr-1 expression -: Role of TNF-α in adiponectin-stimulated interleukin-10 production
Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-α (TNF-α) expression via ERK1/2 activation and Egr-1 expression -: Role of TNF-α in adiponectin-stimulated interleukin-10 production
复制标题
DOI：
10.1074/jbc.m701419200
复制
发表时间：
2007-07-27
影响因子：
4.8
通讯作者：
Nagy, Laura E.
中科院分区：
文献类型：
--
作者：
Park, Pil-hoon;McMullen, Megan R.;Nagy, Laura E.
脂联素是一种具有有效抗炎特性的脂肪因子。然而，脂联素抑制巨噬细胞功能的机制尚不清楚。用脂联素处理 RAW264.7 巨噬细胞 18 小时，可减少脂多糖 (LPS) 刺激的肿瘤坏死因子-α (TNF-α) 的产生。在这里，我们证明球状脂联素（gAcrp）最初增加了 RAW264.7 巨噬细胞中 TNF-α 的表达；这种 TNF-α 会导致白细胞介素 10 的表达增加，而白细胞介素 10 又是对随后的 LPS 暴露产生耐受性所必需的。 gAcrp 介导的 TNF-α mRNA 积累增加与 TNF-α 启动子活性增加相关。 gAcrp 增加了 Egr-1 和 NF kappa B 的 DNA 结合活性； TNF-α 启动子中 Egr-1 或 NF kappa B 结合位点的突变降低了 gAcrp 刺激的启动子活性。此外，与显性失活 Egr-1 或 I kappa B 超级阻遏蛋白共转染可阻止 gAcrp 刺激的 TNF-α 启动子活性。 gAcrp 还增加了 Egr-1 启动子活性、mRNA 积累和 DNA 结合活性。用 U0126 抑制 ERK1/2 可有效抑制 gAcrp 刺激的 Egr-1 启动子活性以及 TNF-α 启动子活性。总之，这些数据表明脂联素最初通过 ERK1/2 -> Egr-1 和 NF kappa B 依赖性机制增加巨噬细胞 TNF-α 的产生； TNF-α 的增加反过来导致白细胞介素 10 的表达增加，并最终抑制巨噬细胞中 LPS 介导的细胞因子的产生。
Adiponectin is an adipokine with potent anti-inflammatory properties. However, the mechanisms by which adiponectin suppresses macrophage function are not well understood. Treatment of RAW264.7 macrophages with adiponectin for 18 h decreased lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) production. Here we demonstrate that globular adiponectin (gAcrp) initially increased TNF-alpha expression in RAW264.7 macrophages; this TNF-alpha then contributed to increased expression of interleukin-10, which in turn was required for the development of tolerance to subsequent LPS exposure. gAcrp-mediated increases in TNF-alpha mRNA accumulation were associated with increased TNF-alpha promoter activity. gAcrp increased the DNA binding activity of both Egr-1 and NF kappa B; mutation of either the Egr-1 or NF kappa B binding sites in the TNF-alpha promoter decreased gAcrp-stimulated promoter activity. Further, co-transfection with either dominant negative Egr-1 or the I kappa B super-repressor prevented gAcrp-stimulated TNF-alpha promoter activity. gAcrp also increased Egr-1 promoter activity, mRNA accumulation, and DNA binding activity. Inhibition of ERK1/2 with U0126 potently suppressed gAcrp-stimulated Egr-1 promoter activity, as well as TNF-alpha promoter activity. In summary, these data demonstrate that adiponectin initially increases TNF-alpha production by macrophages via ERK1/2 -> Egr-1 and NF kappa B-dependent mechanisms; these increases in TNF-alpha in turn lead to increased expression of interleukin-10 and an eventual dampening of LPS-mediated cytokine production in macrophages.