Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
J Immunol. 2011 Apr 1;186(7):4467-73. doi: 10.4049/jimmunol.1003300. Epub 2011 Feb 25.
Subclinical levels of circulating endotoxin are associated with the pathogenesis of diverse human inflammatory diseases, by mildly inducing the expression of proinflammatory mediators. In this study, we examined the molecular mechanism responsible for the effect of low-dose LPS in macrophages. In contrast to high-dose LPS, which activates NF-κB and induces the robust expression of proinflammatory mediators, we observed that low-dose LPS failed to activate NF-κB. Instead, it selectively activated C/EBPδ and removed nuclear repressors, including peroxisome proliferator-activated receptor α and retinoic acid receptor α, enabling a mild and leaky expression of proinflammatory mediators. The effect of low-dose LPS required IRAK-1, which interacts with and acts upstream of IκB kinase ε to contribute to LPS-mediated induction of C/EBPδ and proinflammatory mediators. Additionally, mice fed a high-fat diet acquired elevated levels of endotoxin and proinflammatory mediators in an IRAK-1-dependent fashion. Taken together, these data reveal a distinct pathway preferentially used by low-dose endotoxin in initiating low-grade inflammation.
循环内毒素的亚临床水平与多种人类炎症性疾病的发病机制有关，它通过轻度诱导促炎介质的表达来实现这一作用。在这项研究中，我们研究了低剂量 LPS 在巨噬细胞中产生作用的分子机制。与高剂量 LPS 激活 NF-κB 并诱导强烈的促炎介质表达不同，我们观察到低剂量 LPS 未能激活 NF-κB。相反，它选择性地激活 C/EBPδ，并去除核抑制剂，包括过氧化物酶体增殖物激活受体α和维甲酸受体α，从而实现促炎介质的轻度和渗漏表达。低剂量 LPS 的作用需要 IRAK-1，它与 IκB 激酶ε相互作用，并作用于其上游，有助于 LPS 介导的 C/EBPδ和促炎介质的诱导。此外，喂食高脂肪饮食的小鼠以 IRAK-1 依赖的方式获得了更高水平的内毒素和促炎介质。总之，这些数据揭示了低剂量内毒素在引发低度炎症时优先使用的一种独特途径。
