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Damping the Flames: Inflammation Control Mechanism Determined

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National Institute of Allergy and Infectious Diseases

After a decade of research, Michail Sitkovsky, Ph.D., and

his coworkers at the National Institute of Allergy and

Infectious Diseases (NIAID), may have answered one of the

most perplexing questions in immunology: how the body

limits inflammation. Their finding, that particular cell

surface molecules sense runaway inflammation and tissue

damage, appears in the Dec. 20 issue of the journal

“Nature”.

Inflammation, tissue swelling usually accompanied by pain

and heat, is the body’s generic response to a host of

insults: invasion by bacteria or viruses, injury, or

reactions to one’s own tissues. Within limits, inflammation

is a valuable ally in the body’s fight against invaders.

But left unchecked, inflammation exposes a decidedly

dangerous side. Chronic inflammation is characteristic of

such disorders as asthma, chronic hepatitis, lupus and

rheumatoid arthritis.

Although many drugs lessen or halt inflammation, very

little is known about the body’s own mechanism for

controlling inflammation and the tissue damage that

accompanies it. “Clearly, there must be some way for the

body to shout, ‘Enough already! Stop the inflammation’,”

explains Dr. Sitkovsky. The shout, or signal, must be

sensed and responded to so that inflammatory activity

abates. “We wanted to learn what the signals and sensors

are in living organisms,” he says.

Adenosine and its membrane-bound receptor made attractive

candidates for signal and sensor, Dr. Sitkovsky notes. A

simple molecule that leads a busy life, adenosine is the

core of the cell’s energy-containing compound, ATP, and

elevated levels of it in the brain appear to cause sleep.

Despite its numerous roles throughout the body, adenosine

has received little attention from immunologists, says Dr.

Sitkovsky. “I was pursuing the idea that adenosine has some

important function in the immune system, too,” he says.

This much is known: when tissue damage mounts due to

prolonged inflammation, oxygen levels in the damaged area

fall. This in turn leads to increased amounts of adenosine

outside cells. Dr. Sitkovsky theorized that the excess

adenosine binds to the adenosine receptors, which then

initiate a chain reaction that slows and eventually stops

inflammation. Attractive as they are as candidates,

adenosine and its receptor are just one of many signal-

sensor pairs on the cell’s surface. Any of these might also

be the elusive inflammation-damping mechanism.

To prove the role of adenosine receptors in controlling

inflammation, Dr. Sitkovsky turned to specific genetically

engineered mice. These mice lack adenosine receptors, but

are identical to normal mice in every other way. When

exposed to various inflammatory stimuli (for example, a

drug that mimics virus-induced liver damage), the receptor-

deficient mice suffered extensive tissue damage and in some

cases died, while normal mice were either unaffected or

suffered minimal tissue damage. Further experiments

revealed that no other receptor could substitute for the

adenosine receptor. Mice lacking the critical molecular

brake could not halt either organ-specific or body-wide

inflammation.

“The discovery that adenosine receptors play a central

physiologic role in limiting inflammation is an important

conceptual advance,” says William Paul, M.D., chief of

NIAID’s Laboratory of Immunology, where Dr. Sitkovsky

conducts his research.

“It may help us find new ways to control excessive

inflammation in a wide range of clinical situations. It may

also allow us to develop new ways to enhance the

inflammatory response, when that is desirable, to make

better vaccines and anti-tumor drugs,” Dr. Paul adds.

An additional, provocative finding emerged from Dr.

Sitkovsky’s recent work. When exposed to a caffeine-like

substance, mice in the study had difficulty controlling

acute inflammation. It has been known for many years that

caffeine interferes with the adenosine receptor. If, in

fact, adenosine receptors are needed for effective

inflammation control, anything that hinders their function

might impair the body’s ability to regulate inflammation.

Dr. Sitkovsky plans additional research to see if this

possible caffeine-inflammation connection exists in humans

as well.

NIAID is a component of the National Institutes of Health

(NIH). NIAID supports basic and applied research to

prevent, diagnose, and treat infectious and immune-mediated

illnesses, including HIV/AIDS and other sexually

transmitted diseases, tuberculosis, malaria, autoimmune

disorders, asthma and allergies.

Press releases, fact sheets and other NIAID-related

materials are available on the NIAID Web site at www.niaid.nih.gov.

REFERENCE: A Ohta and M Sitkovsky. Role of adenosine receptors in

downregulation of inflammation and protection from tissue

damage. “Nature” 414: 916-20 (2001).

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