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Little-known substance regulates inflammatory response

In the September 29 issue of the journal Science, researchers from the University of Chicago show that a little-known molecule called A20 plays a critical role in regulating inflammation. This unexpected finding suggests an entirely new target for drugs designed to treat inflammatory diseases such as ulcerative colitis, Crohn's disease, rheumatoid arthritis and even septic shock.

First discovered ten years ago, A20 was largely ignored as an insignificant link in the chain reaction of inflammation. Scientists thought it was only produced by certain types of white blood cells in a few tissues such as the intestines and thymus.

"A20 had been studied in only a limited way at the cellular level and never in a live animal," said Averil Ma, M.D., assistant professor of medicine and immunology at the University of Chicago, who uses transgenic mice to study the basic biology of inflammatory bowel disease.

"We created mice that lacked the A20 gene, hoping to identify its function in intestinal lymphocytes," he said. Instead they discovered that the molecule was much more widespread than anticipated and that it was a critical regulator of inflammation in multiple tissues.

"We found that rapid expression of A20," said Ma, "was absolutely essential for down-regulating the inflammatory response and averting the damage unrestrained inflammation can cause in multiple tissues."

Within three to six weeks after birth, mice without the gene for A20 spontaneously developed severe inflammation and tissue damage in multiple organs. When exposed to substances that mimic infection or trigger inflammation, mice lacking A20 developed symptoms identical to septic shock -- plummeting blood pressure, widespread inflammation, kidney damage, decreased heart function -- and died within two hours. In contrast, normal mice with A20 had no symptoms despite exposure to ten-fold higher doses of these same stimulants.

Inflammation is part of the normal response
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Contact: John Easton
jeaston@uchospitals.edu
773-702-6241
University of Chicago Medical Center
28-Sep-2000


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