Scientists at the Virginia Bioinformatics Institute at Virginia Tech have discovered some of the key molecular1 events in the immune system that contribute to inflammatory（炎症的） bowel2 disease. The results, which help researchers move one step further in their efforts to develop new drugs to treat inflammatory and immune-mediated diseases, are reported in the November 2010 edition (http://www.ncbi.nlm.nih.gov/pubmed/21068720) of the journal Mucosal Immunology from the Nature Publishing Group. Inflammatory bowel disease starts when the gut3 initiates4 an abnormal immune response to some of the one hundred trillion or so bacteria that come into contact with the colon5（结肠） of the human body.
More than 1 million people are affected6 by inflammatory bowel disease in North America alone and direct healthcare expenses for inflammatory bowel disease in the United States are estimated at more than $15 billion annually7.
Earlier mathematical and computational work (http://www.ncbi.nlm.nih.gov/pubmed/20362587) by the scientists pinpointed8 a special type of immune cell as a possible target for intervention9 strategies to fight inflammation-related disease in the gut. The immune cells identified in the earlier work, which are known as M1 or classically activated10 macrophages（巨噬细胞） , cause inflammation and possess a specific molecule11, peroxisome（过氧物酶体） proliferator-activated receptor-gamma, that, when activated, favors a switch to a type of macrophage that reduces the impact of inflammation (alternatively activated macrophage or M2) . The activation12 of the receptor protein and the anti-inflammatory M2 macrophage switch plays a beneficial role in reducing the severity of the disease in the gut during experimentally induced inflammatory bowel disease.
"We have been able to validate13（证实，验证） experimentally some of the key events that take place in the regulation of the mucosal（粘膜的） immune system when inflammatory bowel disease is triggered in mice," said Josep Bassaganya-Riera, associate professor of immunology at the Virginia Bioinformatics Institute, leader of the Nutritional14 Immunology and Molecular Medicine Group in the institute's CyberInfrastructure Division, and principal investigator15. "When we produce mice that lack the peroxisome proliferator-activated receptor-gamma specifically found in macrophages, the severity of inflammatory bowel disease increases significantly. In parallel, we are able to observe the impact of the onset16 of disease on key inflammation-related genes17 and other molecules18 involved in inflammation and metabolism19."
"In this study, we were able to use mouse Affymetrix GeneChips® to examine which genes were turned on and off under disease and non-disease conditions," said Clive Evans, director of the Core Laboratory Facility at the institute. "This gave us a comprehensive snap-shot of what is happening in the immune system of mice when inflammation-related disease takes hold in the gut."
"In addition to our observations of what is happening when inflammatory bowel disease is triggered in mice, we showed that peroxisome proliferator-activated receptor-gamma in macrophages is essential for recovery from disease when the drug pioglitazone（吡格列酮） is used to treat it," said Raquel Hontecillas, assistant professor of immunology at the Virginia Bioinformatics Institute, and lead investigator of the study. "Our group has dissected20 the role of peroxisome proliferator-activated receptor-gamma as an internal thermostat21 for inflammation in other cells involved in gut inflammation such as intestinal22 epithelial cells（上皮细胞） and T cells."
Some of the currently available therapies for the treatment of inflammatory bowel disease in humans are effective in treating the disease but are linked to sometimes-drastic side effects in patients. The researchers hope to use their knowledge of the immune system and specific targets for repurposed drugs and naturally occurring compounds to develop safer alternatives for the long-term management of the disease.
"Our combined computer modeling and experimental validation23 approach, which is part of the work of our Center for Modeling Immunity24 to Enteric Pathogens, is already generating important clinical leads that should help us in our quest to deliver better therapies for infectious enteric（肠的） diseases," concluded Bassaganya-Riera.
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