http://www.osu.edu/researchnews/archive/ratshock.htm
22 August 2001
COLUMBUS, Ohio - Certain social interactions
may weaken the immune system to the point it can't control inflammation,
new research suggests. In turn, the inflammation may cause irreversible
organ and tissue damage.
In a new study, socially stressed
mice were twice as likely to die after exposure to a compound that triggered
an infection-like response as were physically stressed mice.
"The stress somehow triggered an
abnormal immune response to a bacterial toxin," said John Sheridan, a study
co-author and a professor of molecular virology at Ohio State University.
The research appears in a recent
issue of the Journal of Neuroimmunology.
For reasons researchers don't fully
understand, social stress intensified the immune systems' response to a
compound called lipopolysaccharide (LPS). LPS stimulates immune cells to
react as if they were fighting an infection. In the mice, the response
triggered the over-production of pro-inflammatory cytokines, hormones that
regulate immune function.
This sudden onslaught of inflammatory
cytokines caused toxic shock - similar to septic shock in humans - in most
of the socially stressed mice. But these mice remained healthy until they
were injected with LPS. The physically stressed mice didn't have the same
level of inflammation after exposure to LPS.
"Cytokines are strong weapons for
killing bacteria," Sheridan said. "But they're a double-edged sword. While
we need them for everything from wound healing to fighting bacterial and
viral infections, the release of too many, too soon can induce toxic shock."
Mice were put into one of two groups:
either social stress, in which five subordinate mice spent two hours a
day for six days in a cage interacting with an aggressive mouse; or physical
restraint, in which a mouse was confined to a cylindrical tube for 16 hours
without access to food or water.
The researchers compared the mortality
of each group after LPS exposure, and also compared them to accompanying
control groups: caged mice that did not spend time with an aggressive mouse,
and mice that were not confined to a tube, but also did not have access
to food and water.
At the end of the stress experiments,
the researchers injected all of the mice with LPS.
By 48 hours after injection, 75 percent
of the socially stressed mice had developed toxic shock and died, compared
to 35 percent of the physically restrained mice.
In order to compare the effects of
stress on the animals' brains, lungs, livers and spleens, a subset of mice
from each of the four groups was sacrificed 12 hours after injection. All
of the animals had some inflammation in their spleens, but inflammation
in the other organs was negligible in all but the socially stressed and
infected group. In the latter case, the uncontrolled rush of pro-inflammatory
cytokines caused damage to the vital organs.
"Cells from the socially stressed
mice had become resistant to the body's anti-inflammatory mechanisms,"
Quan said.
"It was only when the animal was
infected by the toxin that the resistance manifested itself," Sheridan
said.
In a normal response, anti-inflammatory
hormones called glucocorticoids keep inflammation to a minimum.
The socially stressed mice that received
LPS still produced plenty of glucocorticoids, but were somehow resistant
to the hormones' anti-inflammatory effects (see sidebar). The unchecked
inflammation ultimately damaged the animals' organs. The same effect was
not seen in the physically restrained mice.
"During infection, there is a balancing
act of the immune system," said Ning Quan, a study co-author and an assistant
professor of oral biology at Ohio State. "You want inflammatory cells to
kill the bacteria at the site, but you don't want too many at the site.
"Septic shock is directly associated
with over-inflammation," he said. "Sometimes it's not the infection itself
that kills a person; rather, it's that the body doesn't properly respond
to inflammation."
And social stress isn't necessarily
worse than physical stress when it comes to health. "But social stress
may make certain people more prone to inflammatory diseases," Quan said.
Researchers have noted glucocorticoid
resistance in people with major depression and in those infected with HIV.
"Chronic social stress in these patients
may contribute to the development of glucocorticoid resistance, which could
put these folks at increased susceptibility to inflammatory diseases including
septic shock," he said.
Glucocorticoids are frequently used
to treat patients suffering from inflammatory diseases such as asthma,
rheumatoid arthritis and leukemia. But patients who are resistant to these
hormones don't respond to treatment.
"The effects of glucocorticoid resistance
last for at least 10 days," Sheridan said. "During that time, the animal
is more vulnerable to developing illness and infection."
Grants from the National Institutes
of Health and the John D. and Catherine T. MacArthur Foundation Mind-Body
Network funded this research.
Sheridan and Quan co-authored the
study with Ohio State researchers Ronit Avitsur; Jennifer Stark; Lingli
He; Manisha Shah; Michael Caligiuri; David Padgett; and Phillip Marucha.
Contact: John Sheridan, 614-292-2012;
Sheridan.1@osu.edu
Holly Wagner
Ning Quan, 614-292-1657; Quan.14@osu.edu
Written by Holly Wagner, 614-292-8310;
Wagner.235@osu.edu