Scientists at The Feinstein Institute for Medical Research, in collaboration with colleagues at the Karolinska Institute, have identified the protein signals at the heart of this response, a finding that offers hope for the development of new drugs that selectively block this pathway and prevent sickness syndromes.
The study is published in the latest issue of the Proceedings of the National Academy of Sciences.
Feinstein President Kevin J. Tracey, MD, Karolinska’s Ulf Andersson, MD, and colleagues at both institutions have been mining the immune system pathways that play a critical role in the body’s response to infection and trauma. The pathophysiological response that results in sickness syndrome is mediated by cytokines, molecules that ignite an inflammatory immune response. Most of the time it is a measured response to the conditions at hand, but sometimes the system goes awry and sends out too many inflammatory foot soldiers. The results can be disastrous. Understanding how this process works should lead to effective treatments to prevent sepsis and similar conditions.
In the latest study, Dr. Tracey and his colleagues followed the path of an important cytokine called high-mobility group box 1 (HMGB1,) a housekeeping protein that stimulates the release of other cytokines in response to infection or injury. According to the latest study, HMGB1, which is released during both infection and sterile injury, selectively binds and signals through Toll-like receptor 4 (TLR4), an essential component of the immune system that sets in motion the release of other cytokines which produce sickness syndrome. Surprisingly, they also found that the interaction between these two central proteins (HMGB1 and TLR4) requires a single cysteine, because when they substituted this amino acid for another, the signals leading to cytokine release were blocked.
“These results have implications for the rational design and development of experimental therapeutics for use in sterile and infectious inflammation, because the molecular nature of the interaction is localized to a very small region, encompassing a single amino acid,” the authors wrote. Dr. Tracey added: “This is encouraging for future clinical trials, which are needed to block HMGB1 and stop it from interacting with TLR4 in order to prevent sickness syndrome.”
About The Feinstein Institute for Medical Research: Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson’s disease, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. Feinstein researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org or http://feinsteininstitute.typepad.com/feinsteinweblog/
Jamie Talan, science writer-in-residence
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