title: Induction of IDO by bacille Calmette-Guérin is responsible for development of murine depressive-like behavior.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jason C
authors.initials: JC
authors.lastname: O'Connor
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Lawson
authors.forename: Caroline
authors.initials: C
authors.lastname: André
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Briley
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Szegedi
authors.forename: Jacques
authors.initials: J
authors.lastname: Lestage
authors.forename: Nathalie
authors.initials: N
authors.lastname: Castanon
authors.forename: Miles
authors.initials: M
authors.lastname: Herkenham
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D002908:Chronic Disease; D003863:Depression / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase