Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a “recall-by-genotype” bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD. Author summary Crohn’s disease and ulcerative colitis, characterized by gut inflammation, are the two main subtypes of Inflammatory bowel disease (IBD). Over two hundred genetic loci have been identified that contribute to risk for IBD. However, functional studies are required to determine the mechanisms by which these genetic changes might affect disease risk. To date, only a few IBD loci have been functionally characterized. We focused on the IBD risk locus at TNFSF15 , encoding the cytokine also known as TL1A. Previous work has shown that TNFSF15 enhances lymphocyte activation and promotes inflammation in animal models of disease. However, we here call into question the assumption that TNFSF15 is always a pro-inflammatory molecule by demonstrating that the IBD risk allele at TNFSF15 is associated with decreased production of TNFSF15 by monocytes and macrophages at rest and after stimulation. In addition, we narrow the list of potential variants at TNFSF15 responsible for controlling its expression, and we demonstrate that genetically controlled TNFSF15 can have functional impact on responding T cells. These findings both demonstrate a mechanism by which this IBD risk locus might drive disease predisposition and suggest a new protective role for TNFSF15 in maintaining the intestinal barrier.
【초록키워드】 Monocytes, Inflammation, Macrophage, Ethnic groups, macrophages, T cells, susceptibility, variant, polymorphism, risk, animal model, cytokine, animal models, immunopathology, monocyte, Polymorphisms, RNA, Peripheral blood, Inflammatory bowel disease, lymphocyte, T cell, Genome-wide association studies, Immune homeostasis, Genotype, chronic inflammation, murine model, Genetic variant, receptor, disease, expression, patients, genetic loci, mechanism, IBD, Haplotype, Stimulation, ulcerative colitis, association, TNF, Signaling, Evidence, Hypothesis, Crohn’s disease, Gut, chronic, cell types, cell type, Activation, locus, murine models, protective role, allele, list, risk allele, assumption, protein level, peripheral blood monocytes, compromise, protein levels, decreased expression, predisposition, disease risk, IBD loci, macrophage differentiation, breakdown, upstream, regulatory region, TNFSF15, ENCODE, genetic change, subtype, over, pro-inflammatory, bowel, Affect, intestinal, ENhance, shown, responsible, addition, required, characterized, functional, condition, increase, determine, question, contribute, variety, promote, regulated, expression measurement, healthy volunteer, persist, 【제목키워드】 Macrophage, susceptibility, monocyte, expression,