2. TNF-alpha mediates depressive-like behavior induced by chronic mild stress through upregulation of indoleamine 2,3-dioxygenase in mice

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Major depressive disorder is often preceded by exposure to stressful life events. However, the mechanism of stress facilitating the development of depression is incompletely understood. A role for proinflammatory cytokines and tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in depressive pathology is increasingly getting confirmed. Chronic stress could upregulate proinflammatory cytokines. Therefore, we hypothesized that chronic stress induced depression through specific proinflammatory cytokine and subsequent IDO activation. We explored this hypothesis by analyzing the relationship among depressive-like behavior, inflammatory cytokine level and IDO expression. We used unpredictable chronic mild stress (UCMS) to induce a depressive-like syndromes reflected with decreased sucrose preference, increased immobility in forced swim test and tail suspension test. Results showed that UCMS induced depressive-like behavioral syndrome. Along with the behavior, TNF-alpha protein markedly increased both in plasma and cerebral cortex. IDO was upregulated in the cortex. Pretreating the mice with anti-inflammatory tetracycline derivative minocycline, TNF-alpha antibody infliximab or IDO antagonist 1-methyltryptophan (1-MT) prevented the development of depressive-like behavior. Furthermore, blockage of TNF-alpha inhibited the expression of IDO and protected neurons of cerebral cortex from damage induced by UCMS. These results implicated that TNF-alpha was one of the critical mediator in UCMS-induced depressive-like behaviors, probably through upregulation of IDO and damage of the neurons in cerebral cortex.