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

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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.