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Laboratory of Neurobiologie Intégrative, Formation de Recherche en Evolution Centre National de la Recherche ScientifiqueUnité Mixte de Recherche Institut National de Recherche Agronomique, Institut Franois Magendie, Bordeaux, France
Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana-Champaign
Background.
Activation of the indoleamine 2,3-dioxygenase (IDO) enzyme and the resulting decrease in plasma tryptophan (TRP) levels appears to be a crucial link in the relationship between cytokines and depression. We aimed to develop an experimental model of chronic IDO activation based on bacille Calmette-Guérin (BCG) infection that elicits a robust increase in levels of interferon (IFN), a key cytokine in the activation of IDO.
Methods.
Mice were inoculated intraperitoneally with BCG (107 cfu/mouse). Lung and brain IDO activity was measured over time, together with plasma levels of TRP and IFN-.
Results.
BCG induced, over the course of several weeks, a chronic increase in serum IFN- levels that was associated with a sustained enhancement of lung and brain IDO activity and with decreases in peripheral (serum and lungs) and brain concentrations of TRP, with different time courses between tissues.
Conclusions.
The model of BCG-induced IDO activation will be useful for the study of the consequences of peripheral immune activation in the brain and the role of TRP metabolism in cytokine-induced mood alteration.
The essential amino acid tryptophan (TRP) is the precursor and limiting factor of brain serotonin synthesis [1, 2]. Its degradation along the kynurenine (KYN) pathway yields important neuroactive intermediates that function as N-methyl-d-aspartate receptor ligands [3, 4]. TRP is also an important immunoregulatorits depletion has been associated with the functional loss of T cells and the induction of tolerance [5]. Prolonged alterations in TRP metabolism can therefore have drastic pathophysiological consequences. Decreases in circulating TRP levels have been observed in a wide range of human diseases, particularly those associated with immune activation [4, 6, 7]. Interestingly, recent studies have reported that the development of depressive symptoms, which have been observed in a significant proportion of patients treated with cytokine therapy for cancer or viral diseases, was associated with a profound decrease in serum levels of TRP [8, 9]. These clinical findings have prompted a surge of interest in the study of the mechanisms linking cytokines to TRP metabolism, particularly in the brain, where a reduction in the bioavailability of TRP could affect serotoninergic neurotransmission and play a pathogenic role in the induction of depressive symptoms [10].
In mammals, the initial degradation pathway of TRP depends on 2 different enzymes: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which differ in their tissue localization and regulation [11]. TDO is predominantly expressed in the liver and is mainly activated by corticosteroids. IDO is present in most extrahepatic tissues, including the brain, and is stimulated by proinflammatory cytokines, especially interferon (IFN) [12, 13]. Concurrently, acute cytokine activation transiently inhibits TDO activity [14, 15]. The balance between both enzymes therefore plays a crucial role in the control of peripheral TRP metabolism by immune activation. Moreover, because of its localization in both the peripheral organs and the brain and its regulation by cytokines, IDO could be a crucial link between the immune system and TRP metabolism in the brain [10, 16]. We have previously shown that acute activation of the peripheral innate immune system in mice by the peripheral administration of lipopolysaccharide (LPS) induced a marked but transient activation of IDO in the brain [17]. However, the study of the pathophysiological consequences of any prolonged alteration in TRP metabolism requires a model of chronic brain IDO activation. This has been mainly achieved by use of very potent infectious microorganisms, such as Toxoplasma gondii [18, 19] and malaria parasites [20, 21]. However, their use is associated with severe and even lethal pathological alterations. The aim of the present study was therefore to define a murine model of chronic brain IDO activation within the context of a milder stimulation of the innate immune system.
Bacille Calmette-Guérin (BCG) is an attenuated form of Mycobacterium bovis that is used in several countries to vaccinate against tuberculosis [22]. Intraperitoneal (ip) administration of BCG in mice is rapidly followed by long-lasting mycobacterial dissemination in all organs except the brain [23]. IFN-, the major cytokine induced by mycobacteria [24], is also one of the most important cytokines involved in antimycobacterial immunity [25], as has been shown by the extreme susceptibility to BCG infection of mice lacking functional IFN- or its receptor [26, 27]. Studies of urinary cytokines have also shown that the intravesical administration of BCG, which is at present the most effective treatment for urinary bladder carcinoma [28], induces the production of interleukin (IL)8, IL-2, and IFN- [29]. The mechanism of action of IFN- in controlling and eliminating mycobacteria involves at least 2 processes: the development of a Th1 immune response and the activation of macrophages [30]. This activation is associated with the increased activity of IDO, which contributes to the inhibition of the growth of Mycobacterium avium [31]. On the basis of these findings, we hypothesized that the inoculation of a live attenuated strain of BCG would induce a chronic stimulation of peripheral and brain IDO activity. The results of the present study indicate that this is indeed the case.
MATERIALS AND METHODS
Mice.
Male CD1 mice (7 weeks old) were purchased from IFFA CREDO. They were housed in polypropylene cages under controlled conditions (at 20°C, with lights on from 8:00 A.M. to 8:00 P.M.), in groups of 5, with free access to food and tap water. Mice were handled daily during the acclimatization period, to minimize stress reactions to further manipulation. The study was conducted in accordance with animal-experimentation guidelines and was approved by the local institutional ethical committee.
BCG.
Mice were inoculated with a live attenuated strain of BCG (Connaught strain; ImmuCyst Aventis) that was provided by Pasteur Mérieux. On the day of inoculation, the stock solution was diluted in saline, properly dispersed, and injected ip in a volume of 0.2 mL/mouse. The dose (107 cfu/mouse) was selected on the basis of the literature [32].
Experimental procedure.
Mice were killed by decapitation 7, 15, 22, 26, and 32 days after treatment, within a few seconds after being removed from their home cage. Concomitantly, control mice were killed 7, 22, and 32 days after saline injection. Trunk blood was collected and allowed to clot. After centrifugation (at 4000 g for 15 min at 4°C), aliquots of serum were frozen and stocked at -80°C. Lungs, brain, and liver were also rapidly collected and were immediately homogenized, as described elsewhere [17]. The homogenates were then centrifuged at 14,000 g for 30 min at 4°C, and the supernatants were frozen until assayed.
Measurements of IFN- in serum.
The level of serum IFN- was determined, by ELISA, by use of a commercial kit (OptEIA Set; Pharmingen), according to the manufacturer's protocol. The test sensitivity reached 20 pg/mL.
Assessment of IDO activity.
IDO activity was determined as described elsewhere [14, 17]. Briefly, the reaction was started by the addition of 0.2 mL of the supernatant to 0.8 mL of the reaction mixture (0.4 mmol/L L-TRP, 20 mmol/L ascorbate, 10 mol/L methylene blue, and 100 g of catalase in 50 mmol/L phosphate buffer [pH 6.5]). After 3 h of incubation at 37°C, the reaction was blocked by the addition of 0.2 mL of 30% trichloroacetic acid (TCA). The tubes were further incubated for 30 min at 50°C, to hydrolyze the N-formylkynurenine produced by the reaction to L-KYN. After centrifugation (at 13,000 g for 10 min at 4°C) and ultrafiltration (cutoff, 10,000 Mr), the amount of L-KYN produced from TRP was determined by reversed-phase high-pressure liquid chromatography (RP-HPLC) [33]. One hundred microliters of the supernatant was injected onto a 5-m C18 RP-HPLC column (Lichrospher; Alltech) at a flow rate of 1.0 mL/min with a phase mobile that contained 0.1 mol/L ammonium acetate/acetic acid buffer and 5% acetonitrile (pH 4.65). KYN was detected by UV absorbency at 360 nm. Its retention time, which was determined by use of a solution of L-KYN of known concentration, was 5.5 min. One unit of activity was defined as 1 nmol KYN/h/mg of protein at 37°C. The amount of protein was determined according to the Bradford method [17].
Assessment of TDO activity.
Total enzyme activity was measured in the presence of added hematin (5 mol/L). The crude liver homogenates (0.4 mL) were added to a 1-mL mixture that contained 200 mmol/L potassium phosphate buffer (pH 7.0), 10 mmol/L ascorbic acid, 5 mol/L hematin, and 10 mmol/L TRP. The solution was incubated for 60 min at 37°C. The reaction was stopped by the addition of 0.3 mL of 30% TCA. The solution was shaken at 50°C for 30 min and then centrifuged at 13,000 g for 10 min at 4°C. The quantity of the KYN produced was measured as described above.
Measurements of KYN and TRP.
Two hundred microliters of serum and tissue supernatant was precipitated in 2 mmol/L of TCA. After centrifugation at 13,000 g for 5 min at 4°C, the supernatants were analyzed for their concentration of KYN and TRP as described for the measurement of IDO activity. Levels of KYN and TRP were detected by UV absorbency at 360 and 280 nm, respectively. The detection limit was 2.90 and 2.46 nmol/g of protein for KYN and TRP, respectively.
Statistical analysis.
Means and SEs were calculated at each time point. Data were submitted to a 2-way (treatment × time) analysis of variance, followed by the Student-Newman-Keuls post hoc test.
RESULTS
Serum IFN- levels.
BCG treatment induced a marked increase in serum levels of IFN- that lasted for up to 3 weeks (saline vs. BCG, P < .05) (figure 1A). On day 32, IFN- levels were comparable in both groups (P = .62).
Liver TDO activity.
BCG induced a sustained reduction in TDO activity (saline vs. BCG, P < .0001); the difference was still significant 4 weeks after treatment (saline vs. BCG on day 32, P < .05) (figure 1B). Interestingly, there was an inverse relationship between TDO activity in the liver and lungs (r = -0.54; P < .01) and IDO activity in the brain (r = -0.70; P < .001) in BCG-treated mice. Similarly, significant correlations were also found between TDO activity in the liver and levels of KYN (r = -0.56; P < .005) and TRP (r = 0.74; P < .0001) in lungs, as well as their ratio (r = -0.52; P < .05). As was expected, a significant correlation was also found between TDO activity in the liver and the KYN : TRP ratio (r = 0.65; P < .005).
IDO activity in lungs and brain.
IDO activity in the lungs of saline-treated mice was relatively low but was still twice its baseline level in the brain (14.33 vs. 6.50 pmol/h/g of protein, respectively). BCG induced a drastic and sustained increase in IDO activity in lungs, compared with control mice (saline vs. BCG, P < .0001); this difference was still significant 32 days after treatment (saline vs. BCG, P < .05) (figure 2A). This activation of IDO resulted in a sustained increase in lung (saline vs. BCG, P < .05) and serum (saline vs. BCG, P < .0001) KYN : TRP ratios. IDO activity also increased over time in the brain (BCG × time, F2,35 = 3.3; P < .05), with a maximum on day 22 (saline vs. BCG, P < .001) (figure 2B). IDO activity returned to baseline levels on day 32 (saline vs. BCG, P = .9), unlike what was observed in the lungs. Interestingly, there was a positive relationship between IDO activity in the brain and KYN concentrations in the lungs of BCG-treated mice on day 26 (r = 0.86; P < .05), whereas IDO activation in the brain and lungs by BCG were positively correlated (r = 0.95; P < .005). Moreover, the KYN : TRP ratio in the lungs was correlated with IDO activity in lungs (r = 0.79; P < .0001) and brain (r = 0.55; P < .05) of BCG-treated mice.
KYN and TRP levels.
Brain levels of KYN were below the threshold of detection in both groups (data not shown). KYN concentrations were not significantly altered by BCG treatment in the liver (figure 3C), but they were markedly increased in serum (saline vs. BCG, P < .001; time, F4,28 = 3.5; P < .05) and lungs (saline vs. BCG, P < .001; time, F4,27 = 3.2; P < .05) (figure 3A and 3B). This effect was still significant on day 32 in serum (saline vs. BCG, P < .05), whereas KYN levels in lungs had almost returned to baseline values at that time. Concentrations of TRP in serum, lungs, and the liver were also significantly affected by the treatment. However, the time course and direction of BCG-induced changes were different between tissues. On day 7, BCG induced a significant decrease in TRP levels in serum (saline vs. BCG, P < .05), concomitant with an increase in TRP concentrations in the liver (saline vs. BCG, P < .005). TRP levels thereafter normalized in serum, whereas they remained elevated in the liver (figure 3D and 3F). In contrast, the reduction in TRP levels in the lungs that was induced by BCG (saline vs. BCG, P < .01) was delayed, with a maximal effect on day 26 and a return to baseline values on day 32 (figure 3E). There was no significant overall effect of time or treatment on TRP levels in the brain, but the values measured in BCG-treated mice were significantly lower on day 26 than on days 15 and 32 (546.7 vs. 633.3 and 615.8 nmol/g of protein, respectively; P < .05) (data not shown).
As expected, BCG-induced activation of IDO in the lungs was positively correlated with KYN concentrations in the lungs (r = 0.68; P < .001), and there was a similar correlation between TDO activity in the liver and local levels of KYN (r = 0.60; P < .005). Circulating levels of KYN were positively correlated with KYN levels in the lungs (r = 0.53; P < .01) and liver (r = 0.44; P < .05). In the lungs of BCG-treated mice, TRP levels were negatively correlated with IDO activity (r = -0.78; P < .0001) and KYN concentrations (r = -0.83; P < .0001). In contrast, there was no significant correlation between brain IDO or liver TDO activity and TRP concentrations in the different organs under investigation.
DISCUSSION
The present findings demonstrate that stimulation of the peripheral immune system by BCG in mice leads to chronic activation of IDO in both the lungs and brain. Although the activation of IDO in the lungs had already been observed in mice after inoculation with M. avium [31], the present article is, to our knowledge, the first demonstration of mycobacteria-induced activation of IDO in the brain. The present data are also the first to provide a detailed time-course study of IDO activation over a duration of several weeks. We have already shown an acute activation of IDO in both the lungs and brain of mice by LPS that was subsequent to a marked, but transient, production of IFN- [17]. The present results extend these data further by showing that the chronic production of this cytokine is associated with a sustained increase in IDO activity for several weeks.
There is already evidence that IDO in the brain can be chronically activated in mice by peripheral parasite infections with T. gondii [18, 19] or Plasmodium berghei ANKA or K113 and that this leads to a cerebral and a noncerebral form of malaria, respectively [20, 21]. These infections were associated with severe pathological alterationscerebral malaria is fatal within a few days [34]. The severity of this disease process is not well suited to the study of the functional consequences of long-term IDO activation. In contrast, the BCG strain used in the present study activates the innate immune system, as shown by the sustained production of IFN-, but does not produce severe disease. The organs infected by BCG (mainly the lungs, liver, and spleen) were the same as those infected by those parasites that were used in previous studies [18, 21], but the alterations induced by BCG were much more limited, as has been described elsewhere [35, 36]. BCG inoculation in mice therefore provides a useful model for the study of the mechanisms of chronic alterations in IDO and TDO activity, as well as their consequences for TRP metabolism.
In the present study, BCG-induced activation of IDO was associated with a concomitant inhibition of TDO activity in the liver. Similar alterations in the balance between the activities of these 2 enzymes, but over a shorter period, have already been reported after LPS or pokeweed mitogen treatment [14, 15]. However, the mechanisms underlying these alterations and their physiologic significance are still largely unknown. TDO activity is mainly stimulated by corticosteroids and glucagon as well as by TRP itself, through stabilization of the enzyme [11]. More studies are necessary to elucidate whether the inhibition of TDO induced by BCG is mediated by a possible alteration in corticosterone production.
The main interest of the BCG murine model is to provide information about the relationship between IDO activation in the periphery and the brain. BCG was able to activate IDO in the brain, although to a lesser extent than in the lungs. Increases in IDO mRNA in the brain have already been observed in mice infected with T. gondii [18]. At the periphery, the activation of IDO in a specific organ is usually associated with local growth inhibition of the pathogenic agent, as has been shown for M. avium [31]. In the case of BCG infection, the lungs are the main site of bacteria development; they are therefore a site of intense and sustained immune reaction through the activation of alveolar macrophages. This results in the slow elimination of BCG from lungs [37]. Because BCG does not enter the brain [23], the local activation of IDO is probably secondary to BCG-induced peripheral immune stimulation. IFN- and other cytokines are readily detectable in BCG-stimulated human and murine immunocompetent cell cultures, as well as in the urine of patients treated with intravesical BCG [28, 38]. High circulating concentrations of IFN- have also been observed in animals inoculated with mycobacteria [25, 39]. After intracellular infection, IL-12 originating from macrophages induces Th1 phenotype differentiation and elicits the release of IFN- by Th1 lymphocytes and NK cells [40, 41]. Macrophages, which are a site of IDO activation [31], can also produce IFN- [32]. Whether IFN- is the only cytokine responsible for IDO activation or whether other cytokines, such as tumor necrosis factor [42], are also involved remains to be determined. The mechanisms that account for brain IDO activation in the absence of BCG entering the brain still need to be investigated. Acute peripheral activation of the innate immune system results in the induction of IFN- mRNA by the brain [43], probably via the same mechanisms that account for the transmission of the peripheral proinflammatory message from the periphery to the brain [44].
Although the present data are the first to provide a precise description of the time course of KYN and TRP concentrations in serum, the lungs, the liver, and the brain in response to BCG, they are in line with previous findings obtained in animals infected with T. gondii [19, 42]. As expected, the sustained activation in lung IDO was associated with an important increase in KYN levels in the lungs, which was the direct product of TRP catabolism by IDO. However, levels of KYN in the lungs decreased 4 weeks after treatment, despite still-elevated IDO activity. A similar dissociation between KYN and IDO has already been described [42]. This finding, together with the positive correlation observed between lung and serum levels of KYN, indicates that, after its accumulation in lungs, KYN enters the circulation. Moreover, the correlation observed between levels of KYN in serum and liver suggests that the liver is another source of circulating KYN in BCG-treated mice. In the brain, KYN levels remained below the threshold of detection, despite local IDO activation. Several explanations can account for this difference between the brain and peripheral organs. It could be a simple problem of sensitivity, given that the amount of KYN formed from TRP in the lungs is obviously higher than that in the brain [42]. Another possibility is that levels of KYN are increased only in those brain structures that are richer in IDO than other areas, so that its measurement in the whole brain is diluted. An immunohistochemical study of IDO expression in the brain indeed showed that expression differs from one structure to the next, with high expression in perivascular regions (authors' unpublished data). Still another explanation for the absence of detectable levels of KYN in the brain is that this compound undergoes further metabolism, as has been described elsewhere [14, 15]. These different possibilities are currently under investigation.
Under normal conditions, TRP levels are mainly regulated by the activity of hepatic TDO [45]. However, its regulation is known to be much more complex under conditions of chronic infection [19, 42], as well as during acute TRP depletion [46]. In BCG-treated mice, the lungs become the main site of TRP regulation, as evidenced by the negative correlation between TRP levels and IDO activity in the lungs. As was previously reported for KYN, concentrations of TRP normalize sooner than IDO activity in the lungs. Similarly, the decrease in serum TRP levels is also rapidly corrected. These results indicate that TRP levels are tightly regulated, independently of the KYN pathway metabolism. Under conditions of acute TRP depletion, TRP levels in plasma decrease profoundly until 16 h after the initiation of treatment but return to normal at 24 h [46]. The lack of alimentary TRP is probably compensated by the degradation of albumin and other proteins. TRP concentrations in the brain appear to be more resilient to IDO than TRP activation in peripheral organsthe moderate but sustained increase in IDO activity in the brain induced a marginal reduction in TRP levels only 26 days after BCG treatment. Such a dissociation between the brain and periphery has already been noted [19, 42]. There is always the possibility, as was mentioned earlier, that TRP degradation in the brain occurs in a number of restricted brain areas, so that this effect is diluted when it is measured at the level of the whole brain. To test this possibility, it is necessary to measure the effects of BCG treatment on TRP concentrations in those brain areas in which IDO is expressed the most. Whatever the case, it is clear that further investigations are needed to better understand the different regulation processes that protect the brain from TRP depletion, because alterations in these processes could play a pivotal role in all of the features associated with alterations in TRP, including cytokine-induced depressive symptoms [10]. In summary, the present results show that the murine model of prolonged activation of IDO induced by BCG can be used to study the consequences of peripheral immune activation in the brain and to gain some insight into the role played by the TRP metabolism in the mood alterations associated with a wide range of somatic and psychiatric disorders [10, 47].
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