Regulation of IL-1 production by an E2 ubiquitin conjugase

背景：我们的免疫系统保护我们免受感染。然而，如果免疫系统没有得到适当的调节，它可以启动和延续炎症。白细胞介素1（IL-1）是一种控制免疫系统的蛋白质，维持适量IL-1的问题可能是几种慢性疾病的原因。例如，IL-1可在遗传上易患遗传性发热综合征的个体中引起发热和皮疹。此外，诸如关节炎（1.4%的英国人口）、糖尿病（英国目前有350万例）和肝病类型等疾病也与IL-1产生引发的炎症有关。重要的是，治疗性阻断IL-1可改善许多疾病环境中的症状。然而，随着这些疗法的使用范围扩大，人们也认识到了它们的局限性。因此，重要的是研究IL-1和炎症是如何调节的，以便将来可以设计新的和更好的干预措施。我们最近发现，酶（E2）调节IL-1在人类细胞中的生产。E2减少IL-1的产生，其损失导致IL-1升高。然而，如何E2调节IL-1.Aims和假设：在这个建议中，我们希望更好地了解如何E2分子的作品。我们假设，（i）E2以增强其清除的方式修饰IL-1，（ii）E2活性本身受到密切调节，（iii）E2的遗传丢失将导致更严重的炎症。实验计划：我们将使用现代细胞和生化工具来阐明E2如何调节IL-1。还将研究辅助E2降低IL-1作用的蛋白质。我们建议使用小鼠来研究E2对IL-1和炎症性疾病的影响。我们将对一只小鼠进行基因工程改造，使其缺乏来自特定免疫细胞的E2编码基因。我们将研究这些小鼠如何对引起炎症和类似痛风性关节炎的条件的细菌毒素作出反应。这种遗传方法将提供一个清晰的图像，E2如何在免疫细胞中工作，这些免疫细胞是体内IL-1的主要生产者。总之，我们的工作应该揭示E2如何影响IL-1的产生和全身炎症。由于IL-1与许多自身炎症性疾病的发病机制之间存在因果关系，这项工作将产生广泛的临床和翻译影响。

Background: Our immune system defends us from infections. However, if the immune system is not properly regulated, it can initiate and perpetuate inflammation. Interleukin 1 (IL-1) is a protein that controls the immune system and problems in maintaining the right amount of IL-1 can be a cause for several chronic conditions. For example, IL-1 can cause fever and rashes in individuals genetically susceptible to hereditary fever syndromes. In addition, diseases such as arthritis (1.4 % UK population), diabetes (3.5 million present cases in the UK) and types of liver diseases, are also linked to IL-1 production triggered inflammation. Importantly, therapeutically blocking IL-1 improves symptoms in many diseased settings. However, as the use of these therapies expands, their limitations are also being recognised. It is therefore important to study how IL-1 and inflammation are regulated so that new and better interventions could be designed in the future. We recently identified that an enzyme (E2) regulates IL-1 production in human cells. E2 reduces IL-1 production, and its loss leads to elevated IL-1. However, how E2 regulates IL-1 remains unknown.Aims and hypotheses: In this proposal we wish to better understand how the E2 molecule works. We hypothesize that, (i) the E2 modifies IL-1 in a way that enhances their clearance, (ii) E2 activity is itself closely regulated, and (iii) genetic loss of E2 will lead to more severe inflammation. Experimental plan: We will use modern cellular and biochemical tools to elucidate how E2 regulates IL-1. Proteins that assist E2 in its IL-1-reducing effects will also be studied. We propose to use mice to study the effect of E2 on IL-1 and inflammatory disease. We will genetically engineering a mouse that will lack the gene encoding E2 from specific immune cells. We will study how these mice respond to a bacterial toxin that causes inflammation and conditions that mimic gouty arthritis. This genetic approach will provide a clear picture of how E2 works in immune cells that are the main producers of IL-1 in the body. In summary, our work should uncover how E2 affects IL-1 production and systemic inflammation. This work will have wide-ranging clinical and translational impact due to the causal link between IL-1 and the pathogenesis of many autoinflammatory diseases.