Bacterial DNA and lipopolysaccharide induce synergistic production of TNF-α through a post-transcriptional mechanism
Bacterial DNA and lipopolysaccharide induce synergistic production of TNF-α through a post-transcriptional mechanism
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DOI：
10.4049/jimmunol.166.11.6855
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发表时间：
2001-06-01
影响因子：
4.4
通讯作者：
Morrison, DC
中科院分区：
文献类型：
--
作者：
Gao, JJ;Xue, Q;Morrison, DC
脂多糖具有激活小鼠巨噬细胞产生肿瘤坏死因子-α的能力，是感染性休克等细菌感染相关疾病的重要炎症介质。我们在这里证明，尽管只诱导低水平的肿瘤坏死因子-α，但革兰氏阴性和革兰氏阳性细菌的脱氧核糖核酸与亚阈值浓度的内毒素(0.3 ng/ml)协同作用，在RAW 264.7巨噬细胞样细胞系中诱导肿瘤坏死因子-α。合成的含CpG的寡核苷酸可以模拟细菌DNA的作用，但不能模拟不含CpG的寡核苷酸。任一种DNA预先处理巨噬细胞2-8h可抑制巨噬细胞对DNA/LPS反应产生的肿瘤坏死因子-α。但当预处理时间延长至24 h时，DNA/内毒素对肿瘤坏死因子-α的协同作用进一步增强。RT-PCR分析表明，细菌DNA和内毒素不能协同诱导肿瘤坏死因子-α基因的mRNA水平。对肿瘤坏死因子-α信使核糖核酸半衰期的分析表明，在细菌DNA和内毒素处理的巨噬细胞中，肿瘤坏死因子-α信使的半衰期比细菌DNA或内毒素处理的巨噬细胞要长。这些发现表明，细菌DNA和脂多糖对肿瘤坏死因子-α的时间控制、协同诱导不是在转录水平上介导的。相反，这种协同作用可能通过转录后机制发生。
LPS is well recognized for its potent capacity to activate mouse macrophages to produce TNF-alpha, an important inflammatory mediator in bacterial infection-related diseases such as septic shock. We demonstrate here that while inducing only low levels of TNF-alpha alone, DNA from both Gram-negative and Gram-positive bacteria synergizes with subthreshold concentrations of LPS (0.3 ng/ml) to induce TNF-alpha in the RAW 264.7 macrophage-like cell line. The bacterial DNA effects are mimicked by synthetic CpG-containing oligodeoxynucleotides, but not non-CpG-containing oligodeoxynucleotides. Pretreatment of macrophages with either DNA for 2-8 h inhibits macrophage TNF-alpha production in responses to DNA/LPS. However, when pretreatment was extended to 24 h, DNA/LPS synergy on TNF-alpha is further enhanced. RT-PCR analysis indicates that mRNA levels of the TNF-alpha gene, however, are not synergistically induced by bacterial DNA and LPS. Analyses of the half-life of TNF-alpha mRNA indicate that TNF-alpha message has a longer half-life in bacterial DNA- and LPS-treated macrophages than that in bacterial DNA- or LPS-treated macrophages. These findings indicate that the temporally controlled, synergistic induction of TNF-alpha by bacterial DNA and LPS is not mediated at the transcriptional level. Instead, this synergy may occur via a post-transcriptional mechanism.