Open Access

ARTICLE

TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress

Yu-Ning Liu¹, Yun-Li Peng¹, Lei Liu¹, Teng-Yun Wu¹, Yi Zhang¹, Yong-Jie Lian¹, Yuan-Yuan Yang¹, Keith W. Kelley², Chun-Lei Jiang¹, Yun-Xia Wang¹

1 Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China
2 Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES and Department of Pathology, College ofMedicine, University of Illinois at Urbana-Champaign, 250 Edward R. Madigan Lab, 1201 W. Gregory Drive, Urbana, IL 61801-3873, USA

* Corresponding Authors: Yun-Xia Wang, ; Chun-Lei Jiang,

European Cytokine Network 2015, 26(1), 15-25. https://doi.org/10.1684/ecn.2015.0362

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.

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