title: TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress.
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.
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Liu
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Yun-Li
authors.initials: YL
authors.lastname: Peng
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Lei
authors.initials: L
authors.lastname: -Liu
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Teng-Yun
authors.initials: TY
authors.lastname: Wu
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Lian
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Jiang
authors.affiliation: Department of Psychology and Mental Health, Lab of Stress Medicine, Second Military Medical University, Shanghai 200433, P. R. of China.
authors.forename: Yun-Xia
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D003863:Depression / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019417:Hindlimb Suspension; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007249:Inflammation; D000069285:Infliximab / Q000494:pharmacology; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008911:Minocycline / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020382:Interleukin-18; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D014364:Tryptophan; D000069285:Infliximab; D008911:Minocycline; C525396:1-methyltryptophan
keywords: 3-dioxygenase; TNFα; depression-like behavior; indoleamine 2; minocycline; unpredictable chronic mild stress