The Journal of Neuroscience, April 1, 2009, 29(13):4200-4209; doi:10.1523/JNEUROSCI.5032-08.2009
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Neurobiology of Disease
Interferon-
and Tumor Necrosis Factor-
Mediate the Upregulation of Indoleamine 2,3-Dioxygenase and the Induction of Depressive-Like Behavior in Mice in Response to Bacillus Calmette-Guérin
Jason C. O'Connor,1 *
Caroline André,1 *
Yunxia Wang,1
Marcus A. Lawson,1
Sandra S. Szegedi,1
Jacques Lestage,3
Nathalie Castanon,3
Keith W. Kelley,1,2 and
Robert Dantzer1,2
1Integrative Immunology and Behavior Program, Department of Animal Sciences, College of Agricultural, Consumer and Environmental Sciences and 2Department of Pathology, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, and 3Institut National de la Recherche Agronomique, Centre National de la Recherche Scientifique, Université Victor Segalen Bordeaux II, 33076 Bordeaux, France
Correspondence should be addressed to Robert Dantzer, 227 Edward R. Madigan Laboratory, 1201 West Gregory Drive, University of Illinois at Urbana Champaign, Urbana, IL 61801-3873. Email: dantzer{at}illinois.edu
Although the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), is a pivotal mediator of inflammation-induced depression, its mechanism of regulation has not yet been investigated in this context. Here, we demonstrate an essential role for interferon (IFN)
and tumor necrosis factor (TNF)
in the induction of IDO and depressive-like behaviors in response to chronic immune activation. Wild-type (WT) control mice and IFNR–– mice were inoculated with an attenuated form of Mycobacterium bovis, bacille Calmette-Guérin (BCG). Infection with BCG induced an acute episode of sickness that was similar in WT and IFNR–– mice. Increased immobility during the forced swim and tail suspension tests occurred in WT mice 7 d after BCG inoculation but was entirely absent in IFNR–– mice. In WT mice, these indices of depressive-like behavior were associated with chronic upregulation of IFN, interleukin(IL)-1β, TNF, and IDO. Proinflammatory cytokine expression was elevated in BCG-infected IFNR–– mice as well, but upregulation of lung and brain IDO mRNA was completely abolished. This was accompanied by an attenuation of BCG-induced TNF mRNA and the lack of an increase in plasma kynurenine/tryptophan ratio in the BCG-inoculated IFNR–– mice compared with WT controls. Pretreatment of mice with the TNF antagonist, etanercept, partially blunted BCG-induced IDO activation and depressive-like behavior. In accordance with these in vivo data, IFN and TNF synergized to induce IDO in primary microglia. Together, these data demonstrate that IFN, with TNF, is necessary for induction of IDO and depressive-like behavior in mice after BCG infection.
Received Oct. 17, 2008;
revised Jan. 17, 2009;
accepted Feb. 20, 2009.
Correspondence should be addressed to Robert Dantzer, 227 Edward R. Madigan Laboratory, 1201 West Gregory Drive, University of Illinois at Urbana Champaign, Urbana, IL 61801-3873. Email: dantzer{at}illinois.edu
