@Article{ecn.2015.0362,
AUTHOR = {Yu-Ning Liu, Yun-Li Peng, Lei Liu, Teng-Yun Wu, Yi Zhang, Yong-Jie Lian, Yuan-Yuan Yang, Keith W. Kelley, Chun-Lei Jiang, Yun-Xia Wang},
TITLE = {TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress},
JOURNAL = {European Cytokine Network},
VOLUME = {26},
YEAR = {2015},
NUMBER = {1},
PAGES = {15--25},
URL = {http://www.techscience.com/ECN/v26n1/65553},
ISSN = {1952-4005},
ABSTRACT = {Depression is often preceded by exposure to stressful life events. Chronic stress causes perturbations
in the immune system, and up-regulates production of proinflammatory cytokines, which has been proposed to be
associated with the pathogenesis of clinical depression. However, the potential mechanisms by which stress-induced
proinflammatory cytokines lead to the development of depression are not well understood. Here, we sought to
screen the main proinflammatory cytokines and the potential mechanisms linking inflammation to depression-like
behavior during unpredictable, chronic, mild stress (UCMS), in vivo. Mice were allocated into four groups in each
separate experiment: saline-control, saline-UCMS, drug-control and drug-UCMS. Development of depression-like
behavior was reflected as a reduction in sucrose preference, and increased immobility in both the forced swim and
tail suspension tests. The following drugs were administered intraperitoneally: the pan-anti-inflammatory tetracycline
derivative, minocycline (30 mg/kg, daily), the tumor necrosis factor (TNF)α monoclonal antibody, infliximab
(10 mg/kg, twice weekly), and the indoleamine 2, 3-dioxygenase (IDO) inhibitor, 1-methyltryptophan (1-MT, 10
mg/mouse, daily). Plasma TNFα, IL-1β and IL-18 increased significantly after the four-week UCMS exposure.
Pretreatment of mice with minocycline completely blocked any upregulation. Concurrent with development of
depression-like behaviors, the concentration of TNFα in plasma and the cerebral cortex increased remarkably.
The tryptophan-degrading enzyme IDO was up-regulated in the cortex following UCMS exposure. Treatment of
mice with minocycline, infliximab or 1-MT prevented the development of depression-like behaviors. Furthermore,
blockade of TNFα inhibited expression of IDO and protected cortical neurons from UCMS-induced damage. These
results suggest that TNFα plays a critical role in mediating UCMS-induced depression through up-regulation of
IDO and subsequent damage of cortical neurons.},
DOI = {10.1684/ecn.2015.0362}
}