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Enzyme reins in runaway inflammation; May prove potent drug target


An enzyme found in nearly all animal and human cells acts as a natural brake to prevent potentially deadly runaway inflammation, UCSF scientists have discovered. The discovery in research with mice suggests a promising target for treating a range of inflammatory diseases in which the body’s immune reaction to bacterial invasion spirals out of control, the researchers report.

The enzyme, known as A20, controls the first step in the series of signals that unleash immune system soldiers against a foreign microbe, the scientists found. The enzyme’s action, they discovered, blocks signals from pivotal receptors on immune cells, known as toll-like receptors (TLRs), that directly sense the presence of dangerous bacteria and other microbes.

The research shows that A20 prevents over-reactions of the immune system to blood infections known as sepsis -- a life-threatening condition in which bacteria invade the bloodstream. Unchecked by A20, the new research shows, an over-reactive immune response can lead to a deadly collapse of blood pressure. Because bacteria are plentiful in our intestines, the protein may also control the immune reaction that can cause inflammatory bowel disease, the research shows.

Discovery of the ubiquitous enzyme’s role in shutting down rampant inflammation is being published online August 29 by Nature Immunology.

The research adds to earlier work by the UCSF scientists and colleagues, published in Science, showing that A20 blocks signals triggered by one of the major agents of inflammation -- the immune system’s tumor necrosis factor (TNF). In the new study, the scientists found that mice lacking genes for both the A20 enzyme and TNF still exhibited a high level of inflammation, indicating that the anti-inflammation protection afforded by A20 is at least in part independent of TNF.

"Finding one enzyme that can rein in two potent pathways of inflammation increases the potential benefits of developing drugs to enhance or restore A20’ s effectiveness," said Averil Ma, MD, Rainin Distinguished Professor of Medicine at UCSF and senior author on the Nature Immunology paper.

In addition to restricting inflammation, A20 may also protect tissues from the damage inflammation can cause, Ma said. His group found that A20 protects cells from "programmed cell death," a process by which cells near the site of inflammation may be killed. Many autoimmune diseases such as type 1 diabetes and arthritis involve cell death and damage to tissues caused by programmed cell death, and A20 may naturally prevent this damage, Ma said.

Finally, mounting evidence has linked subtle and chronic states of inflammation with atherosclerosis, the process by which arteries become clogged and lead to heart attacks and strokes. The A20 enzyme may also be a good target to treat these diseases, Ma said.

"Finding that A20 may control multiple important inflammatory processes provides an extremely attractive model -- a lesson from nature -- showing how one might use a single protein to have multiple therapeutic benefits," Ma said. "A drug that mimicked A20’s sundry functions could be extraordinarily useful."

A20 controls inflammation by blocking the immune system’s first line of defense against bacterial attack. When bacteria invade, their carbohydrates bind to TLRs on the surface of macrophages and other immune cells. This initiates a chain reaction of signals in which proteins inside the macrophages are modified. The end result: the macrophages produce and secrete tumor necrosis factor (TNF), interleukin-1 and other cytokines that induce inflammation.

The researchers showed that A20 shuts down one of these signaling proteins, called TRAF6, turning off the immune system cascade. The enzyme, they found, disables the signaling molecule by cleaving off from it a small protein called ubiquitin which would normally activate the signaling molecule.

Recent studies have suggested that ubiquitin modifications may be very important for regulating a wide variety of inflammatory signals within cells. The new research, along with a study by Ma and colleagues published online July 18 by Nature, shows that A20 modifies ubiquitin-containing proteins in two ways, both to deactivate the proteins and remove them.

Wallace Ravven | EurekAlert!
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