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
Journal of Neuroscience. 2009-04-01; 29(13): 4200-4209
DOI: 10.1523/JNEUROSCI.5032-08.2009
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1. J Neurosci. 2009 Apr 1;29(13):4200-9. doi: 10.1523/JNEUROSCI.5032-08.2009.
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.
O’Connor JC(1), André C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N,
Kelley KW, Dantzer R.
Author information:
(1)Integrative Immunology and Behavior Program, Department of Animal Sciences,
College of Agricultural, Consumer and Environmental Sciences, University of
Illinois at Urbana-Champaign, Urbana, Illinois 61801-3873, USA.
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)gamma and tumor necrosis factor (TNF)alpha in the
induction of IDO and depressive-like behaviors in response to chronic immune
activation. Wild-type (WT) control mice and IFNgammaR(-/-) 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 IFNgammaR(-/-) 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 IFNgammaR(-/-) mice. In WT mice, these indices of depressive-like
behavior were associated with chronic upregulation of IFNgamma,
interleukin(IL)-1beta, TNFalpha, and IDO. Proinflammatory cytokine expression was
elevated in BCG-infected IFNgammaR(-/-) mice as well, but upregulation of lung
and brain IDO mRNA was completely abolished. This was accompanied by an
attenuation of BCG-induced TNFalpha mRNA and the lack of an increase in plasma
kynurenine/tryptophan ratio in the BCG-inoculated IFNgammaR(-/-) mice compared
with WT controls. Pretreatment of mice with the TNFalpha antagonist, etanercept,
partially blunted BCG-induced IDO activation and depressive-like behavior. In
accordance with these in vivo data, IFNgamma and TNFalpha synergized to induce
IDO in primary microglia. Together, these data demonstrate that IFNgamma, with
TNFalpha, is necessary for induction of IDO and depressive-like behavior in mice
after BCG infection.
DOI: 10.1523/JNEUROSCI.5032-08.2009
PMCID: PMC2835569
PMID: 19339614 [Indexed for MEDLINE]