Deciphering cathelicidin-induced IL-17F production in the intestine

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In this project we are investigating how white blood cells behave in the intestine, and what controls their behaviour. This is important, because these cells are the key drivers behind inflammatory bowel diseases (IBD) which include Crohn's disease and Ulcerative Colitis. We are trying to work out what makes these cells damaging in some situations and helpful in others. One of the ways we categorise helpful and damaging cells is the type of proteins they produce - particularly proteins called cytokines. Cytokines are important instruction signals which tell cells where to go and how to react to infection. In some cases cytokines are protective, and in others they can be damaging - they can make the cells react too strongly, or to move into the wrong place, which causes damage to tissue like the intestine. Here, we are investigating one particular cytokine, IL-17F. We know that this is present in intestines but we don't really know how it is made, what controls it, nor what it does during disease. We don't know whether it is helpful or damaging in human IBD, although in mice it seems to be very important for driving disease and is therefore a promising therapeutic candidate.We propose that a key driver of IL-17F is a peptide which is released during infection and which kills bacteria, viruses and fungi. This antimicrobial peptide, called cathelicidin, is expressed at high concentration in the intestine. Now, we think that it causes IL-17F to be expressed and that this is one of the ways in which bowel disease begins. In this project we will work out: how cathelicidin causes IL-17F to be expressed, where IL-17F is expressed in the human bowel, and whether cathelicidin-induced IL-17F is important for the development of bowel disease.We will do this through three types of experiments. Firstly, we will use samples that we have collected from healthy people and from patients with IBD. These samples include blood, faeces, and biopsies taken from their small intestine and colon. We will look at these samples and work out how much IL-17F is present, exactly where it is, and which cells make it. Next, we will look at cells in dishes in the lab - from mice and from blood taken from healthy people. We will work out the triggers that drive IL-17F expression from white blood cells and how cathelicidin may be important. Finally, we will usemodels of IBD in mice - we can look at what happens in their intestines when they do not have IL-17F, or cathelicidin. We will carry out all of these experiments at the Centre for Inflammation Research at the University of Edinburgh. Three members of staff will be involved: a postdoctoral fellow to carry out the lab experiments, a bioinformatics specialist who will help crunch the enormous amounts of data this project will involve, and a principal investigator who will run the project and be responsible for data management, safety, keeping records and publishing results.This project will have three important outcomes. It will fully map how IL-17F is expressed in the human intestine for the first time, which is absolutely necessary as we try to understand healthy and damaged intestines in greater detail. It will work out how cathelicidin specifically induces IL-17F, which is interesting and novel immunologically. It will also determine whether this induction of IL-17F by cathelicidin is something we could target as we try to develop novel therapies for IBD. This work will be of interest to immunologists working with cytokines and antimicrobial peptides, to doctors, and to patients with IBD.