Mechanistic role of microRNA-146a in endotoxin-induced differential cross-regulation of TLR signaling.
Mechanistic role of microRNA-146a in endotoxin-induced differential cross-regulation of TLR signaling.
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DOI：
10.4049/jimmunol.1002311
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Chan EK
中科院分区：
文献类型：
--
作者：
Nahid MA;Satoh M;Chan EK
人类 TLR 是微生物成分的关键传感器，可产生受各种机制控制的促炎细胞因子。用 LPS 预处理的单核细胞对同源和异源配体表现出低反应状态，称为交叉耐受，这在先天免疫中发挥着更广泛的作用。迄今为止，LPS 诱导的交叉耐受性尚未在 microRNA 表达动力学方面进行研究。在这项研究中，用各种炎症配体处理的 THP-1 单核细胞显示 microRNA (miR)-146a 在 24 小时内持续扩增，这与 TNF-α 的产生呈负相关。相反，抑制 miR-146a 则显示出交互作用。因此，研究了LPS暴露的THP-1单核细胞中miR-146a的特征性上调的交叉耐受性。引人注目的是，在 LPS 耐受的 THP-1 单核细胞中，只有 miR-146a 显示出持续的过度表达，这表明它在交叉耐受中发挥着至关重要的作用。同样，肽聚糖引发的 THP-1 细胞表现出与 miR-146a 上调相关的同源耐受性。随后，在非 LPS 配体之间观察到可互换的差异交叉调节。 TLR2 和 TLR5 配体表现出与 miR-146a 过表达相关的同源和异源耐受性。更重要的是，由于 miR-146a 靶标 IL-1R 相关激酶 1 或 TNFR 相关因子 6 的敲低，对 TLR4、TLR2 和 TLR5 配体的炎症反应减少，这表明 miR-146a 对这些 TLR 信号传导具有调节作用。将 miR-146a 转染到 THP-1 细胞中会导致 TNF-α 产生减少，模拟 LPS 诱导的交叉耐受性。除了单个配体之外，LPS 引发的 THP-1 单核细胞中的全细菌攻击还伴随着 TNF-α 产量的减少，这与 miR-146a 表达呈相反相关。因此，我们的研究表明，miR-146a 在体外单核细胞内毒素诱导的交叉耐受中发挥着至关重要的作用。
Human TLRs are critical sensors for microbial components leading to the production of proinflammatory cytokines that are controlled by various mechanisms. Monocytes pretreated with LPS exhibit a state of hyporesponsiveness, referred to as cross-tolerance, to both homologous and heterologous ligands, which play a broader role in innate immunity. To date, LPS-induced cross-tolerance has not been examined regarding microRNA expression kinetics. In this study, THP-1 monocytes treated with various inflammatory ligands showed a continuous amplification of microRNA (miR)-146a over 24 h that is inversely correlated to TNF-α production. In contrast, inhibition of miR-146a showed a reciprocal effect. Thus, the characteristic upregulation of miR-146a in LPS-exposed THP-1 monocytes was studied for cross-tolerance. Strikingly, in LPS-tolerized THP-1 monocytes, only miR-146a showed a continuous overexpression, suggesting its crucial role in cross-tolerance. Similarly, peptidoglycan-primed THP-1 cells showed homologous tolerance associated with miR-146a upregulation. Subsequently, interchangeable differential cross-regulation was observed among non-LPS ligands. TLR2 and TLR5 ligands showed both homologous and heterologous tolerance correlated to miR-146a overexpression. More importantly, inflammatory responses to TLR4, TLR2, and TLR5 ligands were reduced due to knockdown of miR-146a targets IL-1R-associated kinase 1 or TNFR-associated factor 6, suggesting the regulatory effect of miR-146a on these TLRs signaling. Transfection of miR-146a into THP-1 cells caused reduction of TNF-α production, mimicking LPS-induced cross-tolerance. Aside from individual ligands, a whole bacterial challenge in LPS-primed THP-1 monocytes was accompanied by less TNF-α production, which is conversely correlated to miR-146a expression. Our studies have thus demonstrated that miR-146a plays a crucial role for in vitro monocytic cell-based endotoxin-induced cross-tolerance.
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发表时间：
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期刊：
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影响因子：
--
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