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
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
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
“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
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).