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，它就会引发并延续炎症。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，白细胞介素-1可在遗传上易患遗传性发热综合征的个体中引起发烧和皮疹。此外，关节炎（英国人口的1.4%）、糖尿病（英国目前有350万例）和各种肝脏疾病也与IL-1的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的症状。然而，随着这些疗法应用的扩大，人们也认识到它们的局限性。因此，研究IL-1和炎症是如何被调节的是很重要的，这样将来就可以设计出新的更好的干预措施。我们最近发现一种酶（E2）调节人类细胞中IL-1的产生。E2减少IL-1的产生，其损失导致IL-1升高。然而，E2如何调节IL-1仍然未知。目的和假设：在这个提议中，我们希望更好地理解E2分子是如何工作的。我们假设，(i) E2修饰IL-1以一种增强其清除率的方式，（ii） E2活性本身受到密切调节，（iii） E2的遗传损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。帮助E2降低il -1的蛋白质也将被研究。我们建议用小鼠研究E2对IL-1和炎性疾病的影响。我们将对一只老鼠进行基因工程改造，使其缺少来自特定免疫细胞的编码E2的基因。我们将研究这些老鼠对细菌毒素的反应，这种毒素会引起炎症和类似痛风性关节炎的情况。这种遗传方法将提供E2如何在免疫细胞中起作用的清晰图像，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的因果关系，这项工作将具有广泛的临床和转化影响。

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.