Induction of IDO by bacille Calmette-Guérin is responsible for development of murine depressive-like behavior

Jason C. O'Connor, Marcus A. Lawson, Caroline André, Eileen M. Briley, Sandra S. Szegedi, Jacques Lestage, Nathalie Castanon, Miles Herkenham, Robert Dantzer, Keith W. Kelley
J Immunol. 2009-02-20; 182(5): 3202-3212
DOI: 10.4049/jimmunol.0802722

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1. J Immunol. 2009 Mar 1;182(5):3202-12. doi: 10.4049/jimmunol.0802722.

Induction of IDO by bacille Calmette-Guérin is responsible for development of
murine depressive-like behavior.

O’Connor JC(1), Lawson MA, André C, Briley EM, Szegedi SS, Lestage J, Castanon N,
Herkenham M, Dantzer R, Kelley KW.

Author information:
(1)Integrative Immunology and Behavior Program, Department of Animal Sciences,
College of Agriculture, Consumer, and Environmental Sciences, University of
Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

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-alpha, IFN-gamma, 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.

DOI: 10.4049/jimmunol.0802722
PMCID: PMC2664258
PMID: 19234218 [Indexed for MEDLINE]

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