Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder

Activation of the inflammatory immune system provokes numerous neuroendocrine and neurotransmitter changes, many of which are similar to those provoked by physical or psychological stressors. These findings, among others, have led to the suggestion that the brain translates immune activation much as if it were a stressor. In this review, I provide synopses of the effects of traditional stressors on the release of corticotropin-releasing hormones at hypothalamic and extrahypothalamic sites, variations of serotonin and its receptors and changes of brain-derived neurotrophic factor (BDNF). These effects are similar to those elicited by activation of the inflammatory immune system, particularly the impact of the immune-signalling molecules interleukin-1 beta, interleukin-6, tumour necrosis factor-alpha and interferon-alpha on neuroendocrine, neurotransmitter and BDNF function. In addition, it is reported that stressors and cytokines may synergistically influence biological and behavioural processes and that these treatments may have long-term ramifications through the sensitization of processes associated with stress responses. Finally, I present an overview of the depressogenic actions of these cytokines in rodent models and in humans, and I provide provisional suggestions (and caveats) about the mechanisms by which cytokines and stressors might culminate in major depressive disorder.