SRC-3 prevents sepsis
By Ruth SoRelle, M.P.H.
A master switch in the cell called steroid receptor coactivator 3 (SRC-3) modulates the immune system's response to bacterial infection, preventing a usually fatal overreaction called endotoxic shock or sepsis, said researchers from Baylor College of Medicine in a report that appears in a recent issue of the journal Molecular Cell.
What is ironic is that in previous experiments, researchers showed that SRC-3 is also necessary to evoke a good inflammatory or immune response, helping to turn on the genes that make cytokines, proteins that fight infection and that can also be part of the cascade of cellular events the lead to shock, said Bert O'Malley, M.D., chair and professor of molecular and cellular biology at BCM and senior author of the report. It now appears that SRC-3 has a dual role that effectively modulates the inflammatory response so that it best benefits the organism – not too much and not too little.
"This is a new concept that is becoming clear in biology. If you have a good protein to do one thing, evolution encourages you to use it again to do other things," he said.
Fighting inflammation
In this case, the finding could present new clues important to the development of new drugs to fight inflammation, an increasingly important field. It also might point the way to new and better treatments for sepsis or toxic shock, said O'Malley.
O'Malley said he and his colleagues were surprised when a mouse that lacked SRC-3 showed an exaggerated inflammatory response to bacteria.
"We thought they would be resistant to it," said O'Malley. "Instead, the mice who did not have it all died. They were more sensitive to the inflammation."
They found that these animals made more cytokines than those who had SRC-3.
"We knew that SRC-3 helped make cytokines," he said. However, other factors help the cell produce those immune system proteins as well.
SRC-3 location affects action
The difference in SRC-3's actions may lie in the area of the cell in which the protein acts.
They found that SRC-3, when it worked in the nucleus, actually induced the production of cytokines, but when it worked in the cytoplasm with the ribosomes – the organelles of the cell that govern the production of proteins – it slowed down the synthesis of the cytokines.
"The protein that boosts the production of cytokines and that you need for rapid, good response so you don't die is also the protein that slows down the response, modifying it so you get enough but not too much. It's doing it in two compartments of the cell. Nothing like this has been identified in a coactivator before. They were mostly thought to work in the nucleus."
"What a beautiful evolutionary control," O'Malley said.
Others who contributed to this report include: Drs. Chundong Yu, Brian York, Shuang, Qin Feng, and Jianming Xu. (Yu is now with the Laboratory of the Ministry of Education for Cell biology and Tumor Cell Engineering at the School of Life Sciences, Xiamen University in China.)
Funding for this study came from the National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute and a National Research Service Award.
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