Magnified Peripheral IL-6 Response Linked To Stress Susceptibility and Higher Risk of Depression

Magnified Peripheral IL-6 Response Linked To Stress Susceptibility and Higher Risk of Depression

A new study published in the Proceedings of the National Academy of Sciences of the USA is perhaps the first to demonstrate that the magnitude of peripheral interleukin (IL)-6 responses preceding stress challenge may confer inter-individual differences in susceptibility or resilience to a subsequent social stressor.

Previous research indicates that in humans both major depression and psychological stress, under certain conditions, are related to increased systemic concentrations of the pro-inflammatory cytokine IL-6 (Maes M, et al., Cytokine, 1997, 11:853; Alesci S, et al., J Clin Endocrinol Metab. 2005, 90:2522). It is not known, however, whether high IL-6 response actually precedes the onset of depression or, alternatively, is the result of the disorder.

In this study, Georgia Hodes et al., as part of an international research team from the US, UK and the Netherlands have used two stress models – social defeat stress (RSDS) and witness defeat stress. Similarly to data in humans, they observed that in mice chronic social subordinations induced a depression-like behavior, such as social avoidance, in a subgroup of mice termed susceptible, whereas resilient mice resisted the development of such behavior.

Measuring cytokine levels after the first exposure to an aggressor in the RSDS model, the authors found that susceptible mice had about a 9-fold increase in IL-6 levels as compared to resilient mice. These results appear clinically relevant and related to other stress paradigms as the authors detected higher IL-6 levels in both humans with treatment-resistant major depressive disorder and mice with chronic variable stress.

The researchers also reported that several days before the experiments and the stress challenge, mice that later developed the susceptible phenotype had increased number of leukocytes (and specifically monocytes), and that these cells released more IL-6 in response to immune challenge. According to the authors this suggests the presence of preexisting individual differences in immune reactivity before RSDS.

The authors conclude that individual differences in the sensitivity of some peripheral immune cells, and more specifically, their IL-6 hyper-responsiveness are preexisting and may determine a greater risk of developing a stress-related disorder, such as depression in a subgroup of susceptible individuals.

Source: Proc Natl Acad Sci U S A. 2014 Oct 20. pii: 201415191. [Epub ahead of print]

Read more: PubMed

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