Determining how sub-cellular localisation of interleukin-1alpha regulates immunity.

炎症是身体对危险的一种反应，比如感染。在炎症期间，免疫系统被激活，巨噬细胞等先天免疫细胞被提醒清除特定的危险，例如病毒，并恢复健康。炎症随着衰老和许多疾病而失调。因此，了解控制炎症的基本机制是非常重要的。巨噬细胞是炎症过程中的重要细胞，因为它们产生分子来协调其他免疫细胞对抗感染。这些分子中最重要的是细胞因子。本项目将研究细胞因子白介素-1 α的作用。这种白细胞介素是独特的，因为它有一个核定位序列，允许它在细胞质和细胞核之间移动。我们认为，这使得这种细胞因子在炎症和感染中发挥双重作用。首先，我们认为运送到细胞核可以防止不必要的细胞因子释放，防止过度和不必要的炎症反应。其次，我们提出白细胞介素-1 α在巨噬细胞产生的其他分子的控制中发挥作用，这些分子对炎症及其消退很重要。为了研究这些假设，我们培育了一只白细胞介素-1 α不能进入细胞核的小鼠，使我们能够区分这些小鼠和白细胞介素-1 α正常的小鼠的炎症反应。此外，我们已经建立了一种技术来检测与白细胞介素-1非常接近的分子，从而可以调节其活性。这项研究将揭示这种细胞因子被调节的新途径和对炎症很重要的新分子。这将是非常有趣的，因为它将产生关于防御感染机制的新知识，这也可能适用于其他研究领域，如衰老或疾病。

Inflammation is a response of the body to danger, such as an infection. During inflammation the immune system is activated and innate immune cells such as macrophages are alerted to remove the specific danger, for example a virus, and restore health. Inflammation is dysregulated with aging as well as during many diseases. Hence it is very important that we understand the basic mechanisms that control inflammation. Macrophages are important cells in the inflammatory process as they produce molecules that coordinate other immune cells to fight infection. The most important of these molecules are called cytokines.This project will investigate the role of the cytokine Interleukin-1alpha. This interleukin is unique, in that it has a nuclear localisation sequence, that allows it to move between the cytosol and the nucleus of the cell. We believe that this allows this cytokine to play a dual role during inflammation, and infection. First, we think trafficking to the nucleus prevents unnecessary release of this cytokine, preventing an excessive and unwanted inflammatory response. Second, we propose that interleukin-1alpha plays a role in controlling production of other molecules produced by macrophages that are important for inflammation and its resolution.To investigate these hypotheses, we have generated a mouse in which interleukin-1alpha cannot enter the nucleus allowing us to differentiate the inflammatory response from these mice, and mice that have a normal interleukin-1alpha. Also, we have established a technique to detect molecules that are very close to interleukin-1alpha and that could therefore regulate its activity. This research will uncover new ways by which this cytokine is regulated and new molecules that are important for inflammation. This will be very interesting as it will result in new knowledge on mechanisms of defence against infection that might also be applicable to other areas of research such as aging or disease.