The inflammatory bowel diseases (IBD) encompassing crohn's disease (CD) and ulcerative colitis (UC) are chronic painful inflammatory conditions of the gastrointestinal tract affecting at least 5 million people worldwide. Generally, inflammation is controlled by particular immune cells together with molecules such as cytokines and lipid mediators. How these molecules work together, however, has been poorly understood. A new study reveals a novel regulation between cytokine IL-10 and lipid mediator PGE2 that functionally connects them to intestinal inflammation.
Published in the Journal of Experimental Medicine, the study shows that IL-10 and PGE2 pathways are intrinsically linked and function as an integrated module to maintain intestinal homeostasis, the balance in our gut. Any disruption to the balance impacts their ability to control macrophage function in the intestine which may have important consequences for both host defence against infection as well as maintenance of intestinal homeostasis.
The project was a collaboration between universities and institutes led by Fiona Powrie, Professor of Musculoskeletal Sciences and Director of the Kennedy Institute at the University of Oxford, Dr Subhankar Mukhopadhyay, Senior Lecturer in Innate Immunity at King's College London, and Professor Gordon Dougan, Glaxo-SmithKline Professor of Microbial Pathogenesis at the University of Cambridge and Former Senior Group Leader at the Wellcome Sanger Institute.
Subhankar commented: "IL-10 is known to promote gut health by preventing immune cells called macrophages from becoming overstimulated by the large number of bacteria that inhabit the gut. Our study reveals that IL-10 fine tunes the secretion of lipid mediator PGE2, preventing inflammatory tissue damage and ensuring that macrophages can kill harmful bacteria effectively."
"Increased PGE2 signalling in the intestine has been reported in IBD patients and the new data suggest that PGE2 may contribute directly to the development and progression of disease. Further examination of this pathway, including the role of distinct PGE2 receptors found on macrophages may open up new therapeutic avenues," said Fiona.
The team studied an infantile onset IBD patient lacking a functional IL10RB gene. It was shown that a loss of IL-10 signaling induced a microbial hyperresponsiveness and over production of PGE2 in macrophages that in turn limited their capacity to kill bacteria, fuelling chronic intestinal inflammation. When introducing functional copies of the IL10RB gene, PGE2 synthesis was inhibited and bacterial killing in macrophages was enhanced showing a regulatory interaction between IL-10 and PGE2.
This study was funded by the Wellcome Trust, and Fondation Louis Jeantet and supported by the NIHR Oxford Biomedical Research Centre, University of Oxford.