Image: University of Chicago Medical Center

The body's immune system is a formidable force. Upon detecting invaders, it launches a no-holds barred attack--the inflammatory response. But once it has the assailants under control, the immune system must reign in the inflammation it caused because, if left unregulated, it can do extensive tissue damage. According to a report published today in the journal Science, researchers have determined that a little-known molecule called A20 plays a key role in quelling inflammation. And the discovery could lead to new treatment for inflammatory diseases such as rheumatoid arthritis and ulcerative colitis.

Thinking that A20 was only produced in a few tissues, researchers at the University of Chicago originally set out to pinpoint A20's function in certain white blood cells in the intestine. In order to do that, they created a line of genetically altered mice that lacked the A20 gene. But a few weeks after birth, these so-called "knockout mice" spontaneously developed serious inflammation and tissue damage in several organs (see photo). Exposing them to inflammation-triggering substances led to septic-shock. Normal mice, in contrast, exhibited no symptoms, even when given 10-fold higher doses of the substances. "We found that A20 was absolutely essential for down-regulating the inflammatory response and averting the damage unrestrained inflammation can cause in multiple tissues," says team member Averil Ma.

Specifically A20 appears to call off a substance known as tumor necrosis factor (TNF). Though critical to the immune response, prolonged release of TNF leads to severe injury. Although the FDA has approved antibodies to TNF for the purposes of treating inflammatory disorders, Ma notes that "these therapies are not always effective." But the discovery of A20's crucial regulatory role should open up new therapeutic avenues. "We can now hope to block cellular responses to TNF," Ma remarks, "in addition to trying to block TNF itself."

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