http://unisci.com/stories/20014/1220015.htm
20-Dec-2001
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 today's 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. - By Anne A. Oplinger
(Reference: A Ohta and M Sitkovsky.
Role of adenosine receptors in downregulation of inflammation and protection
from tissue damage. Nature 414: 916-20 [2001].)
Related website:
NIAID http://www.niaid.nih.gov/
Copyright © 1995-2001 UniSci.
Contact: Anne A. Oplinger