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

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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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Authors and Affiliations

  1. Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, P. R. of China

    Yu-Ning Liu, Yun-Li Peng, Lei- Liu, Teng-Yun Wu, Yi Zhang, Yong-Jie Lian, Yuan-Yuan Yang, Chun-Lei Jiang & Yun-Xia Wang

  2. Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES and Department of Pathology, College of Medicine, University of Illinois at Urbana-Champaign, 250 Edward R. Madigan Lab, 1201 W. Gregory Drive, Urbana, IL, 61801-3873, USA

    Keith W. Kelley

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  1. Yu-Ning Liu
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Correspondence to Chun-Lei Jiang or Yun-Xia Wang.

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Liu, YN., Peng, YL., Liu, L. et al. TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress. Eur Cytokine Netw 26, 15–25 (2015). https://doi.org/10.1684/ecn.2015.0362

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  • DOI: https://doi.org/10.1684/ecn.2015.0362

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