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* Integrative Immunology and Behavior Program, Department of Animal Sciences, College of Agriculture, Consumer, and Environmental Sciences and
Department of Pathology, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
Section on Functional Neuroanatomy, National Institute of Mental Health, Bethesda, MD 20892; and
Institut National de la Recherche Agronomique, Centre National de la Recherche Scientifique, University Victor Segalen Bordeaux II, Bordeaux, France
Chronic inflammation activates the tryptophan-degrading enzyme IDO, which is well known to impair T cell proliferation. We have previously established that bacille Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is associated with persistent activation of IDO in the brain and chronic depressive-like behavior, but a causative role has not been established. In these experiments we used both pharmacologic and genetic approaches to test the hypothesis that IDO activation is responsible for the development of chronic depression that follows BCG infection. BCG induced TNF-
, IFN-
, and IDO mRNA steady-state transcripts in the brain as well as the enzyme 3-hydroxyanthranilic acid oxygenase (3-HAO) that lies downstream of IDO and generates the neuroactive metabolite, quinolinic acid. Behaviors characteristic of depression were apparent 1 wk after BCG infection. Pretreatment with the competitive IDO inhibitor 1-methyltryptophan fully blocked BCG-induced depressive-like behaviors. Importantly, IDO-deficient mice were completely resistant to BCG-induced depressive-like behavior but responded normally to BCG induction of proinflammatory cytokines. These results are the first to prove that the BCG-induced persistent activation of IDO is accompanied by the induction of 3-hydroxyanthranilic acid oxygenase and that IDO is required as an initial step for the subsequent development of chronic depressive-like behavior.
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1 This work was supported by National Institutes of Health Grants R01 AG 029573 (to K.W.K.), R01 MH 71349 (to R.D.), and R01 MH 079829 (to R.D.).
2 Address correspondence and reprint requests to Dr. Keith W. Kelley, 227 Edward R. Madigan Laboratory, 1201 West Gregory Drive, University of Illinois at Urbana-Champaign, Urbana, IL 61801-3873. E-mail address: kwkelley{at}illinois.edu
3 Abbreviations used in this paper: BCG, bacille Calmette-Guérin; Ct, threshold cycle; FST, forced swim test; 3-HAO, 3-hydroxyanthranilic acid oxygenase; ISH, in situ hybridization; KAT, kynurenine aminotransferase; KMO, kynurenine 3-hydroxylase; Kynu, kynureninase; 1-MT, 1-methyl tryptophan; TST, tail suspension test; WT, wild type.
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  J. C. O'Connor, C. Andre, Y. Wang, M. A. Lawson, S. S. Szegedi, J. Lestage, N. Castanon, K. W. Kelley, and R. Dantzer Interferon-{gamma} and Tumor Necrosis Factor-{alpha} Mediate the Upregulation of Indoleamine 2,3-Dioxygenase and the Induction of Depressive-Like Behavior in Mice in Response to Bacillus Calmette-Guerin J. Neurosci., April 1, 2009; 29(13): 4200 - 4209. [Abstract] [Full Text] [PDF]
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