More MS news articles for Aug 2001

Social Stress may Trigger Problems in Immune System

22 August 2001
Holly Wagner

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;
Ning Quan, 614-292-1657;
Written by Holly Wagner, 614-292-8310;