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Long Intergenic Noncoding RNA Associated with Kawasaki Disease

Sanford-Burnham Medical Research Institute scientists have discovered a new molecule that forms when certain white blood cells—macrophages—are stimulated in response to pathogens. The molecule, termed "THRIL," helps regulate the immune response and shows an association with Kawasaki disease. The findings suggest that THRIL may contribute to other inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. The study, published online on December 26, 2013 in PNAS, measured large intergenic noncoding RNA (lincRNA) produced when the immune system is activated. One lincRNA was found to bind heterogenous nuclear ribonucleoprotein L (hnRNPL), creating a new molecule that regulates genetic control of TNF-alpha—a potent cytokine that promotes inflammation. The authors named the molecule THRIL, after TNF-alpha and hnRNPL-related immunoregulatory lincRNA. Large noncoding RNA corresponds to the parts of the genome that do not code for protein. "For some time we have known that noncoding regions of RNA play important roles in regulating the immune response to microbial pathogens," said Tariq Rana, Ph.D., senior author of the study and professor in the Sanford Children's Health Research Center and director of the RNA Biology Program at Sanford-Burnham. "When we realized that THRIL functioned to control the TNF-alpha gene, we wanted to see if it mirrors the progression in inflammatory diseases." Collaborating with Jane Burns, M.D., professor of pediatrics at Rady Children's Hospital and the University of California-San Diego (UC San Diego), Dr. Rana's team measured THRIL levels in Kawasaki disease samples at different stages of the disease, and found that levels were at their lowest during the acute stage of the disease—when TNF-alpha levels are at their highest. The findings suggest that THRIL could be a novel biomarker for immune activation and a potential target for inflammatory diseases. The study was co-authored by Dr. Zhonghan Li, Sanford-Burnham Medical Research Institute; Dr. Ti chun Chao, Sanford-Burnham Medical Research Institute; Dr. Kung-Yen Chang, Sanford-Burnham Medical Research Institute; Dr. Nianwei Lin, Sanford-Burnham Medical Research Institute; Dr. Veena Patil, Sanford-Burnham Medical Research Institute; Dr. Chisato Shimizu, Department of Pediatrics, Rady Children's Hospital San Diego and UC San Diego; Dr. Steven R. Head, The Scripps Research Institute; Dr. Jane C. Burns, Department of Pediatrics, Rady Children's Hospital San Diego and UC San Diego; and Dr. Tariq M. Rana, Sanford-Burnham Medical Research Institute and UC San Diego. TNF-alpha is a signaling protein produced mainly by macrophages in the body's response to infection. TNF-alpha is known to drive inflammation and tissue destruction in immune mediated diseases. Anti-TNF drugs are used to control inflammatory diseases such as rheumatoid arthritis and psoriasis. Macrophages are the first line of defense for the immune system, and are considered to be the "bottom feeders" of white blood cells. They work by ingesting many cells and, depending on the type of cell ingested, they send signals—such as TNF-alpha—to alert the rest of the immune system that it's time to defend the body. Kawasaki disease is a rare childhood disease that involves inflammation of the blood vessels. In some cases, the disease affects the coronary arteries, leading to serious heart problems. Kawasaki disease affects children of all races, genders, and ages. It occurs most often in children of Asian and Pacific Island descent. Symptoms include red eyes, red lips, and redness on the palm of their hands and soles of their feet—all signs of inflamed blood vessels. The cause of the disease is unknown, and there is no known prevention. Although the disease has a good prognosis with treatment, it can lead to death from coronary artery aneurysm in a small percentage of patients. [Press release] [PNAS abstract]