Foxo1 increases pro-inflammatory gene expression by inducing C/EBPβ in TNF-α-treated adipocytes
Foxo1 increases pro-inflammatory gene expression by inducing C/EBPβ in TNF-α-treated adipocytes
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DOI：
10.1016/j.bbrc.2008.11.043
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发表时间：
2009-01-09
影响因子：
3.1
通讯作者：
Fukamizu, Akiyoshi
中科院分区：
文献类型：
--
作者：
Ito, Yu;Daitoku, Hiroaki;Fukamizu, Akiyoshi
肥胖与脂肪组织中的低度炎症有关，该炎症是由于促炎细胞因子的产生增加而引起的，并且随后导致胰岛素抵抗的发展。然而，促炎基因转录调控的机制仍不清楚。在这里，我们发现肿瘤坏死因子 (TNF)-α 治疗减弱了 Foxo1 的 Akt 依赖性磷酸化并增强了 Foxo1 的转录活性。我们发现 Foxo1 通过直接与其启动子结合，增加了 CCAAT/增强子结合蛋白（C/EBP beta，单核细胞趋化蛋白（MCP）-1 和白细胞介素（IL）-6 基因的正调节因子）的表达。此外，Foxo1 和 C/EBP beta 的敲低可抑制 3T3-L1 脂肪细胞中 TNF-α 诱导的 MCP-1 和 IL-6 的表达。这些发现表明， Foxo1 由 TNF-α 触发，上调 3T3-L1 脂肪细胞中 C/EBP beta 的表达，从而导致促炎细胞因子、MCP-1 和 IL-6 的产生增加 (c) 2008 Elsevier Inc，保留所有权利。
Obesity is associated with a low-grade inflammation in adipose tissue resulting from increased production of pro-inflammatory cytokines and which call subsequently contribute to the development of insulin resistance. However, the mechanisms underlying the transcriptional regulation of pro-inflammatory genies are Still Unclear. Here we show that tumor necrosis factor (TNF)-alpha treatment attenuated Akt-dependent phosphorylation of Foxo1 and enhanced transcriptional activity of Foxo1. We found that Foxo1 increased the expression of CCAAT/enhancer binding protein (C/EBP beta a positive regulator of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 genes, through directly binding to its promoter. Furthermore, knockdown of Foxo1 as well as C/EBP beta inhibits TNF-alpha-induced expression of MCP-1 and IL-6 in 3T3-L1 adipocytes. These findings suggest that activation of Foxo1 triggered by TNF-alpha up-regulates the expression of C/EBP beta in 3T3-L1 adipocytes, thereby leading to all increased production of pro-inflammatory cytokines, MCP-1 and IL-6. (c) 2008 Elsevier Inc, All rights reserved.