Drawing on lab experiments and computer studies, Johns
Hopkins researchers have learned how a common protein
delivers its warning message to cells when an infectious
agent invades the body. The findings are important because
this biological intruder alarm causes the body's immune
system to leap into action to fight the infection. Learning
more about how this process works, the researchers said,
could lead to better treatments for diseases that occur
when the immune system overreacts or pays too little
attention to the infection alarm.
Collaborating with colleagues at the University of
California, San Diego, the Johns Hopkins researchers have
used their discoveries to develop a new computer model that
could help produce medications for immune system-related
ailments including septic shock, cancer, lupus and
rheumatoid arthritis.
Their findings, which focused on how a large protein
molecule called tumor necrosis factor, or TNF, triggers an
immune response, were reported in the February issue of The
Journal of Biological Chemistry.
"We were surprised by how sensitive cells were to
small amounts and brief exposures to TNF," said
Andre
Levchenko, a Johns Hopkins assistant professor of
biomedical
engineering and senior author of the paper. "Our
analysis may help drug companies solve problems with the
regulation of immune response levels, and do it in a smart
way."
In particular, Levchenko's team looked at the innate
immune response, a localized reaction that normally stops
an infection threat confined to a small part of the body,
such as in the case of a pricked finger. (This is in
contrast to a systemic response that triggers an immune
reaction throughout the body, causing a fever. If the
immune system responds too aggressively in such cases, the
result may be a dangerous condition called septic
shock.)
The innate immune response begins when white blood
cells detect a bacterial intruder or toxin in the body.
They produce TNF to carry a message about this health
threat to neighboring blood vessel cells, asking them to
join in the fight. To send this message, a TNF molecule
latches onto the surface of a neighboring cell and accesses
a biological information highway called the NF-kappaB
pathway. Via a series of chemical reactions that act like
signals traveling over a telephone wire, TNF's message
moves along this pathway from the cell's surface to its
nucleus.
At the end of this pathway, NF-kappaB molecules are
released to carry the alarm into the nucleus, the cell's
control center. Inside the nucleus, the NF-kappaB molecules
switch on genes that produce infection-fighting proteins.
These proteins launch several strategies to fight the
microscopic invaders, such as sending more white blood
cells to engulf the bacteria or toxins. The proteins also
set off a response known as inflammation, characterized by
redness, swelling and pain.
In their journal article, Levchenko and his colleagues
reported several important new discoveries about this
cellular signaling system. "You could think of the TNF
molecule, which sounds the alarm, as a very weak radio
transmitter. It moves very slowly as it carries its warning
message to neighboring cells, so it is unable to send that
message over long distances," Levchenko said. "However, we
discovered that the cellular pathways that pick up this
signal act like extremely sensitive radio receivers. They
can pick up the alarm message from exposure to even a very
small amount of TNF. This turns out to be a very smart
strategy on the part of the cells."
He explained that a pricked finger usually generates a
very localized fight against infection, involving only
nearby cells. If TNF's signal was strong enough to set off
an immune response involving the entire body, the result
could be a high fever and septic shock. "We've developed a
better understanding of why the fight against a local
infection stays local," said Raymond Cheong, a graduate
student in Levchenko's lab and lead author of the journal
article.
The researchers also found that as TNF's warning
message travels from the surface of a cell to its nucleus,
it receives critical help from a molecule called inhibitor
of kappaB kinase, or IKK. "IKK filters and interprets the
warning message," said Cheong, who is an M.D.-Ph.D.
candidate in the School of Medicine. "It carefully controls
the level of the immune system's response."
That makes IKK a very promising target for new
medications designed to boost or suppress the immune
system, the researchers said. An overactive immune system,
for example, can set off the excessive inflammation
associated with rheumatoid arthritis and lupus. In
addition, some cancers are more likely to grow where
inflammation occurs. These ailments might be helped by a
drug that curbs inflammation by reducing the sensitivity of
IKK. Still other diseases that are characterized by a weak
inflammatory response might be helped by a drug that makes
IKK even more sensitive to infection messages.
The researchers believe their computer model of this
cellular alarm system, which was refined through lab
testing, should be a great help to medication makers.
"Models like this are a wonderful tool for experimental
drug testing," Levchenko said.
Funding for the research was provided by the National
Institutes of Health and the Medical Scientist Training
Program at Johns Hopkins. Co-authors of the journal article
include Adriel Bergmann, a graduate student in the
Department of Biomedical Engineering at Johns Hopkins; and
Shannon L. Werner, Joshua Regal and Alexander Hoffman, all
of the Signaling Systems Laboratory, Department of
Chemistry and Biochemistry, University of California, San
Diego.