Enzyme Reins In Runaway Inflammation; May Prove Potent Drug Target

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Source: University Of California - San Francisco

2004-08-31

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.

Lead author on the Nature Immunology paper is L. Boone, UCSF assistant

adjunct professor of gastroenterology working with Ma's lab.

Co-authors on the paper and collaborators in the research are Emre ,

MA; G. Lee, BA; and Regina-Celeste Ahmad, BA; and a Hurley, BA, all

graduate students in medicine at UCSF; T. Wheeler, BA, graduate

student in medicine at University of Chicago; Colleen Tsui, BA, graduate

student in biochemistry and molecular biology, School of Public Health,

s Hopkins University; Marcia Chien, BA, and Sophia Chai, BA, both senior

research technicians in Ma's lab; and Osamu Hitotsumatsu, MD, postdoctoral

fellow in medicine at UCSF; McNally, MD, associate professor of

medicine, University of Chicago; and Cecile Pickart, PhD, professor of

biochemistry and molecular biology at s Hopkins University.

The research was supported by grants from the National Institutes of Health.