Molecular Mechanisms Responsible for the Selective and Low-Grade Induction of Proinflammatory Mediators in Murine Macrophages by Lipopolysaccharide
Molecular Mechanisms Responsible for the Selective and Low-Grade Induction of Proinflammatory Mediators in Murine Macrophages by Lipopolysaccharide
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DOI：
10.4049/jimmunol.1200857
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发表时间：
2012-07-15
影响因子：
4.4
通讯作者：
Li, Liwu
中科院分区：
文献类型：
--
作者：
Maitra, Urmila;Deng, Hui;Li, Liwu
低剂量内毒素血症在具有不良健康状况的人类中普遍存在，并且其与慢性炎性疾病如动脉粥样硬化、糖尿病和神经系统炎症的发病机制相关。然而，对潜在的分子机制知之甚少。在这项研究中，我们证明了亚临床低剂量LPS通过细胞表面TLR 4，IL-1 R相关激酶-1和Toll相互作用蛋白将巨噬细胞扭曲成轻度促炎状态。与高剂量LPS不同，低剂量LPS不会诱导NF-κ B、MAPK、PI 3 K或抗炎介质的强烈活化。相反，低剂量LPS通过Toll相互作用蛋白介导的线粒体活性氧的产生来诱导激活转录因子2，从而允许轻度诱导促炎介质。低剂量LPS还抑制PI 3 K和相关的炎症基因负调节因子。我们的数据揭示了导致偏斜和持续性低度炎症的新机制，这是慢性炎症性疾病的主要特征。免疫学杂志，2012，189：1014-1023。
Low-dose endotoxemia is prevalent in humans with adverse health conditions, and it correlates with the pathogenesis of chronic inflammatory diseases such as atherosclerosis, diabetes, and neurologic inflammation. However, the underlying molecular mechanisms are poorly understood. In this study, we demonstrate that subclinical low-dose LPS skews macrophages into a mild proinflammatory state, through cell surface TLR4, IL-1R-associated kinase-1, and the Toll-interacting protein. Unlike high-dose LPS, low-dose LPS does not induce robust activation of NF-kappa B, MAPKs, PI3K, or anti-inflammatory mediators. Instead, low-dose LPS induces activating transcription factor 2 through Toll-interacting protein-mediated generation of mitochondrial reactive oxygen species, allowing mild induction of proinflammatory mediators. Low-dose LPS also suppresses PI3K and related negative regulators of inflammatory genes. Our data reveal novel mechanisms responsible for skewed and persistent low-grade inflammation, a cardinal feature of chronic inflammatory diseases. The Journal of Immunology, 2012, 189: 1014-1023.