Yuyan Cheng, Richard S Jope, Eleonore Beurel

Major depressive disorder is a prevalent disease that is inadequately treated with currently available interventions. Stress increases susceptibility to depression in patients and rodent models. Depression is also associated with aberrant activation of inflammation, such as increases in circulating levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα). The two main goals of this study were (i) to identify cytokine changes measuring a broad panel of 19 cytokines, and (ii) to test if a pre-conditioning stress altered the inflammatory response to a subsequent stress. Stress-induced changes in mouse plasma cytokines were measured by multiplex following administration of one or two daily stresses of inescapable foot shocks using the learned helplessness paradigm for modeling depression-like behavior. Administration of inescapable foot shocks increased plasma levels of IL-1β, IL-6, TNFα, IL-3, IL-10, IL-13, IL-17A, IL-5, GM-CSF, IL-12(p70), IFN-γ, MIP-1α, MIP-1β, IL-1α, IL-2, KC, RANTES and G-CSF, with peak levels occurring in the range of 6 to 12 hr after stress. Pre-conditioning the mice 24 hr before with an equivalent inescapable foot shock stress resulted in similar magnitudes of increases in most cytokines as occurred after a single stress, but accelerated the increase, causing the levels of most cytokines to peak 1 hr after stress. These results demonstrate that a single stress induces the expression of many cytokines, and that sequential, daily stresses accelerates the rate of cytokine production. Acute stress broadly activates inflammation in mice, and the inflammatory response is more rapid following repeated stress, actions that may contribute to deleterious effects of stress on depression and other stress-linked diseases.