Key Molecule in Inflammation-Related Depression Confirmed

March 20, 2009 • Science Update

Scientists have confirmed the role of an immune-activated enzyme in causing inflammation-related depression-like symptoms in mice. The work clarifies how the immune system can trigger depression and, more broadly, demonstrates the potential of this animal model for exploring the relationship between chronic inflammation—a common feature of diseases such as heart disease, cancer, and diabetes—and depression.

Background

When an individual is infected with viruses or bacteria, cells of the immune system respond by secreting proteins called cytokines. These cytokines not only trigger inflammation and orchestrate the body's immune response against the infection, but they also cause changes in behavior, such as fatigue and withdrawal. Beyond these commonly experienced behavioral signs of illness, previous research has shown that cytokines can also cause depression in people with physical illnesses but who have no prior history of mental illness. For instance, around one-third of patients receiving the cytokine interferon-α for treatment of cancer or hepatitis C develop major depression. Clinical evidence has suggested that an enzyme (IDO) activated by these same cytokines might be a key player.

This Study

In this work, scientists used a weakened form of the tuberculosis relative, bacille Calmette-Guérin (BCG), to model chronic inflammation. This strain of bacteria is used outside the U.S. as a vaccine for tuberculosis. Infection of mice with high doses of BCG persistently activates the immune system; as a consequence, the mice develop depressive-like behavior after initial signs of illness have subsided. This study demonstrated that mice in which the gene for IDO is knocked out, or in which IDO is chemically blocked, do not exhibit depressive-like effects. The authors conclude that IDO is a necessary step in the development of this immunity-related depression.

Significance

The compound used in this work to block IDO may have potential as a treatment for depression in instances when immunotherapy such as interferon-α is used. In addition, chronic, low-grade inflammation is a feature not only of infectious diseases, but conditions like cancer, diabetes, obesity, and heart disease. Depression co-occurs frequently with these common diseases and is associated with poorer prospects for future health. Work in this animal model has the potential to provide insight into the role of chronic inflammation in precipitating depression that is often associated with these chronic conditions.

Scientists at the University of Illinois, Urbana-Champaign, led by Jason O'Connor, Robert Dantzer, and Keith Kelley, conducted this work with collaborators at the Centre National de la Recherche Scientifique, Bordeaux, France, and Miles Herkenham at the National Institute of Mental Health. The National Institute of Mental Health and the National Institute on Aging funded this research.

What's Next

The use of BCG in this mouse model offers a means to explore the molecular cascade induced by IDO that leads to inflammation-associated depression. The exact mechanism by which IDO causes these depressive behaviors is not yet clear; exploration of the downstream effects of IDO may provide additional avenues for developing approaches to blocking the development of immune-related depression.

Reference

O'Connor, J.C., Lawson, M.A., Andre, C., Briley, E.M., Szegedi, S.S., Lestage, J., Castanon, N., Herkenham, M., Dantzer, R., and Kelley, K.W. Induction of IDO by Bacille Calmette-Guerin Is Responsible for Development of Murine Depressive-Like Behavior. Journal of Immunology 2009 Mar 1;182(5):3202-12. PMID: 19234218