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.
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