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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Induction of nuclear factor-κB responses by the S100A9 protein is Toll-like receptor-4-dependent
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Induction of nuclear factor-κB responses by the S100A9 protein is Toll-like receptor-4-dependent

机译：S100A9蛋白诱导的核因子-κB反应是Toll样受体4依赖性的

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摘要

Interactions between danger-associated molecular patterns (DAMP) and pathogen-associated molecular patterns (PAMP) and pattern recognition receptors such as Toll-like receptors (TLRs) are critical for the regulation of the inflammatory process via activation of nuclear factor-κB (NF-κB) and cytokine secretion. In this report, we investigated the capacity of lipopolysaccharide (LPS) -free S100A9 (DAMP) protein to activate human and mouse cells compared with lipoprotein-free LPS (PAMP). First, we showed that LPS and S100A9 were able to increase NF-κB activity followed by increased cytokine and nitric oxide (NO) secretion both in human THP-1 cells and in mouse bone marrow-derived dendritic cells. Surprisingly, although S100A9 triggered a weaker cytokine response than LPS, we found that S100A9 more potently induced IκBα degradation and hence NF-κB activation. Both the S100A9-induced response and the LPS-induced response were completely absent in TLR4 knockout mice, whereas it was only slightly affected in RAGE knockout mice. Also, we showed that LPS and S100A9 NF-κB induction were strongly reduced in the presence of specific inhibitors of TLR-signalling. Chloroquine reduced S100A9 but not LPS signalling, indicating that S100A9 may need to be internalized to be fully active as a TLR4 inducer. This was confirmed using A488-labelled S100A9 that was internalized in THP-1 cells, showing a raise in fluorescence after 30 min at 37°. Chloroquine treatment significantly reduced the fluorescence. In summary, our data indicate that both human and mouse S100A9 are TLR4 agonists. Importantly, S100A9 induced stronger NF-κB activation albeit weaker cytokine secretion than LPS, suggesting that S100A9 and LPS activated NF-κB in a qualitatively distinct manner.
机译：危险相关分子模式（DAMP）与病原体相关分子模式（PAMP）和模式识别受体（如Toll样受体（TLR））之间的相互作用对于通过激活核因子-κB（NF）调节炎症过程至关重要-κB）和细胞因子分泌。在本报告中，我们研究了无脂多糖（LPS）的S100A9（DAMP）蛋白与无脂蛋白LPS（PAMP）相比激活人和小鼠细胞的能力。首先，我们表明LPS和S100A9能够增加人THP-1细胞和小鼠骨髓来源的树突状细胞中NF-κB的活性，然后增加细胞因子和一氧化氮（NO）的分泌。出人意料的是，尽管S100A9引发的细胞因子反应比LPS弱，但我们发现S100A9更有效地诱导IκBα降解，从而诱导NF-κB活化。在TLR4基因敲除小鼠中完全不存在S100A9诱导的反应和LPS诱导的反应，而在RAGE基因敲除小鼠中仅受到轻微的影响。此外，我们显示在存在TLR信号转导的特异性抑制剂的情况下，LPS和S100A9NF-κB的诱导作用大大降低。氯喹减少了S100A9的表达，但没有降低LPS信号的传递，表明S100A9可能需要内在化才能完全发挥TLR4诱导剂的作用。使用在THP-1细胞中内在化的A488标记的S100A9证实了这一点，在37°30分钟后荧光增强。氯喹处理显着降低了荧光。总之，我们的数据表明人和小鼠S100A9都是TLR4激动剂。重要的是，尽管S100A9诱导的NF-κB激活比LPS弱，但其细胞因子分泌较弱，这表明S100A9和LPS在质性上激活了NF-κB。

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