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Down-regulation of IRAK-4 is a component of LPS- and CpG DNA-induced tolerance in macrophages

机译：IRAK-4的下调是巨噬细胞中LPS和CpG DNA诱导的耐受性的组成部分

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Macrophages are important mediators of the immune response to infection by virtue of, amongst other things, their ability to secrete cytokines (e.g. TNF) that trigger inflammation. However, excessive systemic release of inflammatory cytokines can cause septic shock and ultimately death. Tolerance is an adaptive mechanism that prevents macrophage activation and inflammatory cytokine production. The activation of macrophages by pathogens is largely mediated by Toll-like receptors (TLRs). IRAK-4 and IRAK-1 are proximal protein kinases in TLR signalling pathways; IRAK-1 is activated via its phosphorylation by IRAK-4. The rapid degradation of IRAK-1 following its TLR-induced activation has been proposed to represent a major mechanism for tolerance. Here, we established that IRAK-1 degradation is insufficient to cause tolerance; in the absence of IRAK-1, IRAK-4 likely activates downstream signalling proteins (e.g. NF-kappa B) via IRAK-2. Significantly, tolerance coincided with IRAK-4 down-regulation, which occurred at the protein level via proteolytic degradation as well as at the mRNA level. Gene silencing experiments confirmed the importance of IRAK-4 for the regulation of TNF expression. The different kinetics of IRAK-4 and IRAK-1 down-regulation may result in both quantitative and qualitative differences in TLR signalling and potentially allow macrophages to temporally modify their inflammatory responses. Furthermore, differences in the kinetics and extent of IRAK-4 down-regulation by TLR ligands may provide a mechanism whereby macrophages can tailor their inflammatory response according to the location and/or type of pathogen detected. (c) 2008 Elsevier Inc. All rights reserved.
机译：巨噬细胞由于其分泌触发炎症的细胞因子（例如TNF）的能力而成为感染免疫反应的重要介体。然而，炎性细胞因子的全身过度释放会引起败血性休克并最终导致死亡。耐受是防止巨噬细胞活化和炎性细胞因子产生的适应性机制。病原体激活巨噬细胞主要由Toll样受体（TLR）介导。 IRAK-4和IRAK-1是TLR信号通路中的近端蛋白激酶。 IRAK-1通过IRAK-4的磷酸化被激活。已提出IRAK-1在TLR诱导的激活后迅速降解，代表了耐受的主要机制。在这里，我们确定IRAK-1降解不足以引起耐受性。在没有IRAK-1的情况下，IRAK-4可能会通过IRAK-2激活下游信号蛋白（例如NF-κB）。重要的是，耐受性与IRAK-4下调相吻合，IRAK-4下调发生在蛋白水平上，通过蛋白水解降解，也发生在mRNA水平上。基因沉默实验证实了IRAK-4对于调节TNF表达的重要性。 IRAK-4和IRAK-1下调的不同动力学可能导致TLR信号传导在数量和质量上都不同，并可能使巨噬细胞暂时改变其炎症反应。此外，TLR配体对IRAK-4下调的动力学和程度的动力学差异可提供一种机制，使巨噬细胞可根据检测到的病原体的位置和/或类型来调节其炎症反应。 （c）2008 Elsevier Inc.保留所有权利。

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