By Roberta Attanasio
Stress and anxiety are part of life — but while a little bit of stress (good stress) may keep us active and alert, and sometimes even motivate us, the long-term type (bad stress) can have negative effects on our health. Elevated blood pressure and heart disease are just some examples of the so-called “stress-related diseases”. In addition, chronic stress increases the risk of developing depression.
Scientists have known for many years that stress, anxiety and depression are linked to the inflammatory response — our first line of defense against infectious microbes. The link is provided by some of the chemical messengers, or cytokines, involved in this response. Patients with major depressive disorder and post-traumatic stress disorder produce higher levels of the cytokine interleukin 6 (IL-6). Is depression responsible for the increased cytokine levels, or are the increased cytokine levels responsible for the development of depression? Results from a new study published in the scientific journal Proceedings of the National Academy of Sciences (November 11, 2014) help to answer this question.
The study (Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress) was carried out by researchers at the Icahn School of Medicine at Mount Sinai (and their collaborators), using mice exposed to social stress. The researchers measured levels of IL-6 in mice prior to and after exposure to “repeated social defeat stress” and stress induced by witnessing the defeat of another mice. In experiments that involve repeated social defeat stress, non-aggressive mice are repeatedly subjected to bouts of social defeat by a larger and aggressive mouse placed in the same cage. In experiments based on stress induced by witnessing, mice watch another mouse face a larger, more aggressive mouse through a clear divider — this type of stress is considered purely emotional. When exposed to social stress, some of the non-aggressive mice, the so-called susceptible mice, develop a clear depressive-like syndrome, which is characterized by long-lasting deficits in social interactions. termed “social avoidance” — mice prefer to spend more time near an empty cage rather than near another mouse.
The researchers found that IL-6 levels are higher in mice more susceptible to stress than in unstressed mice or in mice more resilient to stress. They also found that, in stress-susceptible mice, numbers of white blood cells that release IL-6 are higher than numbers in control groups. Moreover, the researchers found increased levels of IL-6 in two separate groups of human patients diagnosed with treatment-resistant major depressive disorder, thus validating the results obtained with mice.
In additional experiments, the researchers transplanted a group of mice with white blood cells lacking IL-6, and treated another group of mice with antibodies that block the production of IL-6. Then, they exposed the mice to stress. Their findings show that, in both groups of mice, the development of social avoidance is reduced, suggesting that the emotional response to stress can be generated or blocked by IL-6. Together, results from the study indicate that the levels of IL-6 produced prior to stress exposure may be responsible for susceptibility or resilience to social stress. In other words, increased IL-6 levels may drive the development of depression.
Scott Russo, the leader of the research team, said in a press release: “Interleukin-6 could be a risk factor for the development of depression in vulnerable individuals. We believe our studies could have significant impact on the development of new antidepressant therapeutics that inhibit IL-6, which may reduce stress-induced relapse in patients with major depressive disorder.”
In their paper, the researchers point out that the differences between stress-susceptible and stress-resilient mice are not genetic and might be due, instead, to environmental factors.