Spatio-temporal differences in the profile of murine brain expression of proinflammatory cytokines and indoleamine 2,3-dioxygenase in response to peripheral lipopolysaccharide administration

https://doi.org/10.1016/j.jneuroim.2008.06.011Get rights and content

Abstract

The mechanisms underlying in vivo activation of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme that mediates in the brain the induction of depressive-like behavior by peripheral innate immune system stimulation are still poorly understood. By monitoring how cytokines parallel IDO mRNA expression in the brain in response to intraperitoneal lipopolysaccharide injection in mice, we report a time-dependent induction of IDO expression in both the hippocampus and hypothalamus that was associated with a specific structure-dependent expression of proinflammatory cytokines, particularly interferon-γ. This study suggests that different mechanisms regulate the activation of IDO by lipopolysaccharide in various brain structures.

Introduction

During an infection, proinflammatory cytokines produced in the periphery by activated innate immune cells induce the production of the same molecular signals by microglial cells and macrophage-like cells in the brain (Dantzer et al., 2006). These brain cytokines organize the subjective, behavioral and metabolic components of the sickness response that allows the organism to cope with infectious micro-organisms (Konsman et al., 2002). The host response to infection can be induced experimentally by the administration of lipopolysaccharide (LPS), the active component of endotoxin from Gram-negative bacteria. LPS induces a strong production of both peripheral and brain proinflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor-necrosis factor-α (TNFα) (Castanon et al., 2004, Gatti and Bartfai, 1993, Laye et al., 1994, van Dam et al., 1998). Brain IL-1β is a key cytokine for orchestrating the development of sickness behavior (Kent et al., 1992, Laye et al., 2000). When immune activation continues unabated, exacerbation of the sickness response can, in some conditions, culminate in the development of depressive symptoms (Capuron and Dantzer, 2003). Since the intensity of these symptoms is correlated to a drastic fall in plasma levels of the essential amino acid tryptophan, it has been proposed that this drop could be due to enhanced activation of indoleamine 2,3-dioxygenase (IDO) (Dantzer et al., 2008). In mice, the acute behavioral symptoms of sickness that are induced by LPS are replaced by depressive-like behaviors appearing 24 h post-treatment (Frenois et al., 2007). These changes coincide with maximal stimulation of brain IDO activity by LPS (Lestage et al., 2002). The role of IDO in the development of depressive-like behavior is apparent from experiments involving direct blockade of LPS-induced IDO activation with 1-methyltryptophan. This IDO antagonist abrogates depressive-like behavior, but not sickness behavior (O'Connor et al., in press).

In mammals, the extrahepatic enzyme, IDO, is the first and rate-limiting enzyme of tryptophan catabolism along the kynurenine pathway (Taylor and Feng, 1991). It is expressed in human and mouse macrophages and dendritic cells, as well as in brain endothelial cells, astrocytes, microglia and neurons (Carlin et al., 1989, Guillemin et al., 2005, Kwidzinski et al., 2005). Mounting evidence indicates that interferon-gamma (IFNγ) is an essential factor for the induction of IDO (Brown et al., 1989, Byrne et al., 1986). Conversely, IFNγ-induced IDO activation is postulated to be one of the key mechanisms underlying the anti-microbial, anti-viral and anti-proliferative properties of this cytokine (King and Thomas, 2007, Mellor and Munn, 2004). The activation of IDO following a peripheral parasite infection is abolished in IFNγ-deficient mice (Fujigaki et al., 2002, Silva et al., 2002), whereas intraperitoneal injections of IFNγ stimulate IDO activity (Saito et al., 1991, Saito et al., 1992). In addition, the IDO gene promoter possesses the different elements required for its induction by IFNγ (Sotero-Esteva et al., 2000). However, both in vitro and in vivo studies show that in some conditions other proinflammatory cytokines can also contribute to the induction of IDO by acting either in synergy with IFNγ, as shown for TNFα (Babcock and Carlin, 2000, Robinson et al., 2006, Robinson et al., 2003), or by IFNγ-independent mechanisms (Fujigaki et al., 2001, Saito et al., 1996). In particular, a transcriptional synergistic activation of IDO by IL-1β, TNFα and IL-6 has been reported in human monocytic THP-1 cell cultures exposed to LPS (Fujigaki et al., 2006).

Although these data provide important insights into the mechanisms underlying increased IDO activity in peripheral immune cell lines, much less is known about the mechanisms involved in the in vivo induction of brain IDO by stimulation of peripheral innate immune cells. We have recently shown that in LPS-treated mice increased brain IDO activity was associated with an increased transcription of IDO mRNA concomitant with increased production of plasma IFNγ and IL-6 (Godbout et al., in press, Lestage et al., 2002). Moreover, targeting peripheral and brain proinflammatory cytokine expression via the administration of the anti-inflammatory tetracycline derivative minocycline blocked LPS-induced brain IDO activation (O'Connor et al., in press). Based on these findings, we hypothesized that brain IDO activation by peripheral LPS administration could be mediated by local expression of IFNγ and/or one or more of the other proinflammatory cytokines induced by LPS, particularly TNFα, IL-1β or IL-6. In order to test this hypothesis, the present set of experiments was carried out to determine the effect of LPS on the temporal pattern of expression of cytokines and IDO in two key structures for brain cytokine expression and action: the hypothalamus and hippocampus (Castanon et al., 2004, Frenois et al., 2007, Laye et al., 1994, Schiepers et al., 2005) up to 24 h post-LPS. We report here that LPS induced a time-dependent increase in IDO expression in both the hippocampus and hypothalamus that was associated with a specific structure-dependent induction of proinflammatory cytokines by LPS.

Section snippets

Animals and treatment

Male CD1 mice 7-week old were purchased from Charles River Laboratories. They were housed individually under a normal 12-h light/dark cycle (7:00 on). Food and water were available ad libitum and room temperature was controlled (23 ± 1 °C). Mice were handled daily for at least one week before the onset of the experiment to minimize stress reactions to manipulation. All animal care and use were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NRC) and approved by

Effect of peripheral LPS challenge on body weight and lung IDO enzymatic activity

In order to verify the effectiveness of LPS treatment, we measured in saline- and LPS-treated mice both the time course of body weight change, over time, compared to pre-treatment body weight (Fig. 1A) and lung IDO activity as assessed by the KYN/TRP ratio 2, 6, 12 and 24 h after LPS injection (Fig. 1B). As expected, LPS induced a progressive and sustained decrease in body weight in all treated mice compared to saline-treated controls [treatment: F(1,40) = 86.29, p < 0.001; time: F(3,40) = 10.74, p < 

Discussion

Although LPS-induced IDO activity in peripheral immune cell lines has been extensively studied in vitro, the mechanisms underlying in vivo activation of peripheral, and overall brain IDO by peripheral stimulation of innate immune cells are still poorly understood. Furthermore, although it is widely accepted that IFNγ is the major inducer of IDO at the periphery, its potential expression in the brain, as well as its implication in the in vivo activation of brain IDO, have not been clearly

Acknowledgments

This study was funded by INRA, CNRS, Région Aquitaine, the French Ministry of Research (ACI “Neurosciences Intégratives et Computationnelles” to NC) and National Institutes of Health (NIH) to KWK (MH-51569 and AG-029573) and RD (R01 MH-71349 and MH-079829).

References (61)

  • LawsonL.J. et al.

    Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain

    Neuroscience

    (1990)
  • LayeS. et al.

    Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice

    Brain Res. Mol. Brain Res.

    (1994)
  • LestageJ. et al.

    The enzyme indoleamine 2,3-dioxygenase is induced in the mouse brain in response to peripheral administration of lipopolysaccharide and superantigen

    Brain Behav. Immun.

    (2002)
  • MingamR. et al.

    In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain

    Brain Behav. Immun.

    (2008)
  • MitoN. et al.

    Change of cytokine balance in diet-induced obese mice

    Metabolism

    (2000)
  • RobinsonC.M. et al.

    NF-kappa B activation contributes to indoleamine dioxygenase transcriptional synergy induced by IFN-gamma and tumor necrosis factor-alpha

    Cytokine

    (2006)
  • SaitoK. et al.

    Chronic effects of gamma-interferon on quinolinic acid and indoleamine-2,3-dioxygenase in brain of C57BL6 mice

    Brain Res.

    (1991)
  • SaitoK. et al.

    Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse

    Neuroscience

    (1992)
  • SavchenkoV.L. et al.

    Microglia and astrocytes in the adult rat brain: comparative immunocytochemical analysis demonstrates the efficacy of lipocortin 1 immunoreactivity

    Neuroscience

    (2000)
  • SchiepersO.J. et al.

    Cytokines and major depression

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2005)
  • ZhaoC. et al.

    TNF-alpha knockout and minocycline treatment attenuates blood-brain barrier leakage in MPTP-treated mice

    Neurobiol Dis.

    (2007)
  • Alberati-GianiD. et al.

    Expression of the kynurenine enzymes in macrophages and microglial cells: regulation by immune modulators

    Amino Acids

    (1998)
  • AmarS. et al.

    Diet-induced obesity in mice causes changes in immune responses and bone loss manifested by bacterial challenge

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • BrownR.R. et al.

    Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2

    Cancer Res.

    (1989)
  • ByrneG.I. et al.

    Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells

    Infect Immun.

    (1986)
  • CapuronL. et al.

    Cytokines and depression: the need for a new paradigm

    Brain Behav. Immun.

    (2003)
  • CarlinJ.M. et al.

    Interferon-induced indoleamine 2,3-dioxygenase activity inhibits Chlamydia psittaci replication in human macrophages

    J. Interferon. Res.

    (1989)
  • CurrierA.R. et al.

    Tumor necrosis factor-alpha and lipopolysaccharide enhance interferon-induced antichlamydial indoleamine dioxygenase activity independently

    J. Interferon Cytokine Res.

    (2000)
  • DantzerR. et al.

    Inflammation, sickness behaviour and depression

  • DantzerR. et al.

    From inflammation to sickness and depression: when the immune system subjugates the brain

    Nat. Rev., Neurosci.

    (2008)
  • Cited by (0)

    View full text