Macrophages sense pathogens via DNA motifs: Induction of tumor necrosis factor-alpha-mediated shock
Macrophages sense pathogens via DNA motifs: Induction of tumor necrosis factor-alpha-mediated shock
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DOI：
10.1002/eji.1830270712
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发表时间：
1997-07-01
影响因子：
5.4
通讯作者：
Wagner, H
中科院分区：
文献类型：
--
作者：
Sparwasser, T;Miethke, T;Wagner, H
病原体的细胞表面成分，例如脂多糖（LPS），是受体介导的免疫细胞激活的重要信号。在这里，我们证明革兰氏阳性和革兰氏阴性细菌的DNA或某些显示未甲基化CpG基序的合成寡核苷酸可以在体外触发巨噬细胞诱导核因子-κB的核转位，积累肿瘤坏死因子（TNF）-κmRNA并释放大量TNF-κ。在体内，这些事件最终导致急性细胞因子释放综合征，其中包括 TNF-α 的全身性但短暂的积累。 D-半乳糖胺 (D-GalN) 致敏小鼠因巨噬细胞衍生的 TNF-α 导致肝细胞爆发性凋亡而死于致命的中毒性休克。通过 TNF-α 释放测量，LPS 和特定寡核苷酸在体内协同作用，表明巨噬细胞整合了各自的信号。巨噬细胞通过快速释放促炎细胞因子来区分和响应细菌DNA的能力可能指出了一种重要但尚未被认识的外源DNA传感机制。
Cell surface components of pathogens, such as lipopolysaccharide (LPS), are an important signal for receptor-mediated activation of immune cells. Here we demonstrate that DNA of gram-positive and gram-negative bacteria or certain synthetic oligonucleotides displaying unmethylated CpG-motifs can trigger macrophages in vitro to induce nuclear translocation of nuclear factor-kappa B, accumulate tumor necrosis factor (TNF)-kappa mRNA and release large amounts of TNF-kappa. In vivo these events culminate in acute cytokine-release syndrome which includes systemic but transient accumulation of TNF-alpha. D-Galactosamine (D-GalN)-sensitized mice succumb to lethal toxic shock due to macrophage-derived TNF-alpha resulting in fulminant apoptosis of liver cells. LPS and a specific oligonucleotide synergized in vivo as measured by TNF-alpha-release, suggesting that macrophages integrate the respective signals. The ability of macrophages to discriminate and to respond to bacterial DNA with acute release of proinflammatory cytokines may point out an important and as yet unappreciated sensing mechanism for foreign DNA.