In experiments with genetically engineered mice, Johns Hopkins researchers have found an "off-switch" for systemic inflammation, the body's overall response to injury and infection. The findings may have implications for treatment of inflammation-related diseases in humans, from autoimmune disorders to atherosclerosis, the researchers say.
Unlike the case in normal mice, in mice bred not to have the "off-switch," an injection of inflammation-causing proteins led to fatal kidney failure, the result of uncontrolled systemic inflammation. Studies have also revealed which genes were affected by the missing off-switch, a protein called stat3-beta, says Stephen Desiderio, M.D., Ph.D., an author of the report in the Feb. 8 issue of Cell.
Future studies may prove some of those affected genes, or even stat3-beta itself, to be good targets for treating abnormal systemic inflammatory responses, the researchers say. In humans, systemic inflammation is reflected in general malaise, the sensation of not feeling well.
"This general inflammation helps keep us alive until the immune system builds specific tools like antibodies to fight off germs or other invaders," says Desiderio, a Howard Hughes Medical Institute (HHMI) investigator at Hopkins and professor of molecular biology and genetics.
"It takes a whole host of molecules to respond to the initial injury or infection, but that response can be lethal if it goes on too long. In the mice we studied, stat3-beta shuts off that response," he adds. "Stat3-beta's role in humans is likely to be quite similar, although the details will no doubt differ."
In both mice and humans, stat3-beta regulates various genes, turning them on or off. The researchers found that, in normal mice, a sharp spike in stat3-beta's activity comes shortly after inflammation begins. In mice engineered to lack stat3-beta, experiments showed that more than 120 genes were expressed at higher levels than normal, sugge
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
7-Feb-2002