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